Hydrophobically tagged small molecules as inducers of protein degradation

ABSTRACT

Provided are bifunctional small molecules of Formula (I): 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, wherein M represents a small organic molecule which binds, covalently or non-covalently, a kinase, such as Her3 protein kinase; L 1  represents a linker; and R H  represents a hydrophobic group. An example of a compound of Formula (I) is a compound of Formula (II): 
     
       
         
         
             
             
         
       
     
     Also provided are pharmaceutical compositions comprising a compound of Formula (I) or (II) and methods of using such compounds for treating proliferative diseases.

RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) to U.S.provisional patent application, U.S. Ser. No. 61/716,305, filed Oct. 19,2012, the entirety of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Inducing protein degradation using hydrophobic tags is a strategy thathas recently received active attention from the scientific community.For example, Crews and co-workers discovered that covalent attachment ofa hydrophobic tag to a dehalogenase fusion protein is effective inmodulating the level of the transgenic fusion protein. See, e.g.,Neklesa et al., Nature Chemical Biology (2011) 7:538-543. Hydrophobictags used to induce protein degradation may eventually be found usefulin a variety of applications, such as, for example, tagged therapeuticagents and tagged research tools for inducing protein degradation invivo and in vitro. However, the development of such hydrophobicallytagged agents and tools is underrealized and continues to remain ofgreat interest.

SUMMARY OF THE INVENTION

The present invention is based on the development of bifunctionalcompounds (i.e., a kinase binding small molecule tagged with ahydrophobic moiety) that can induce the degradation of a kinase ofinterest. These bifunctional compounds possess a kinase recognitionelement that can bind either covalently or non-covalently and a‘hydrophobic’ tag element that signals to the intracellular proteinhomeostasis machinery to induce degradation of the targeted kinase. Incontrast to all currently reported small molecule approaches tomodulating kinase activity which typically involve inhibition ofenzymatic activity, these bifunctional compounds are designed to inducethe physical elimination of the protein from the cell. Without wishingto be bound by any particular theory, the protein degradation induced bythe bifunctional compounds studied appears to be dependent upon themolecular chaperone protein Hsp90 and/or on the proteasome, the centralproteolytic enzyme in the cell.

Bifunctional compounds contemplated herein are generally represented byFormula (I):

or a pharmaceutically acceptable salt thereof;wherein:

M represents a small organic molecule which binds to a kinase;

L¹ represents a linker selected from the group consisting of substitutedand unsubstituted alkylene, substituted and unsubstituted alkenylene,substituted and unsubstituted alkynylene, substituted and unsubstitutedheteroalkylene, substituted and unsubstituted heteroalkenylene,substituted and unsubstituted heteroalkynylene, substituted andunsubstituted heterocyclylene, substituted and unsubstitutedcarbocyclylene, substituted and unsubstituted arylene; substituted andunsubstituted heteroarylene, and combinations thereof; and

R^(H) represents a hydrophobic group selected from the group consistingof substituted and unsubstituted aryl, substituted and unsubstitutedheteroaryl, substituted and unsubstituted carbocyclyl, substituted andunsubstituted heterocyclyl, substituted and unsubstituted aralkyl,substituted and unsubstituted heteroarylalkyl, substituted andunsubstituted carbocycylalkyl, and substituted and unsubstitutedheterocyclylalkyl.

Binding of a small molecule M refers to covalent or non-covalent bindingto a kinase, e.g., a protein kinase. In certain embodiments, Mcovalently binds a protein kinase. In other embodiments, Mnon-covalently binds a protein kinase. Exemplary kinases are listedherein. In certain embodiments, M represents a small organic moleculewhich covalently or non-covalently binds to Her3 kinase.

The small organic molecule M is substituted with a group -L²-R^(D),wherein:

L² represents a bond or a linker selected from the group consisting ofsubstituted and unsubstituted alkylene; substituted and unsubstitutedalkenylene; substituted and unsubstituted alkynylene; substituted andunsubstituted heteroalkylene; substituted and unsubstitutedheteroalkenylene; substituted and unsubstituted heteroalkynylene;substituted and unsubstituted heterocyclylene; substituted andunsubstituted carbocyclylene; substituted and unsubstituted arylene;substituted and unsubstituted heteroarylene; and combinations thereof;and

R^(D) is of the formula:

wherein Y, X¹, R^(D1), R^(D2), R^(D3), R^(D4), and z are as defineherein.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof; wherein Ring A, R^(B),R^(C), R^(D), R^(H), L¹, L², a, and b are as defined herein.

In certain embodiments, Ring A is substituted or unsubstituted phenyl.In certain embodiments, Ring A is a substituted or unsubstituted 5- to6-membered heteroaryl ring. In certain embodiments, Ring A is asubstituted or unsubstituted C₃₋₈ carbocyclyl ring. In certainembodiments, Ring A is a substituted or unsubstituted 3- to 8-memberedheterocyclyl ring.

In certain embodiments, R^(H) is a substituted or unsubstitutedhydrophobic group of formula:

wherein R^(H1), R^(H2), R^(H3), q, and p are as defined herein.

In certain embodiments, L¹ represents a linker 4 to 20 consecutivecovalently bonded atoms in length, inclusive. In certain embodiments, L¹represents a linker 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutivecovalently bonded atoms in length.

In certain embodiments, L¹ represents a linker consisting of acombination of one or more groups of the formulae:

wherein n, m, Q, W, G₁, G₂, R^(W1), R^(W2), and R^(W3) are as definedherein.

In certain embodiments, the compound of Formula (I) has a molecularweight of between about 200 to about 800 g/mol, inclusive. In certainembodiments, the compound has a c Log P less than 5, e.g., between about−8 to about 4.9 c Log P, inclusive. In certain embodiments, the compoundhas 0, 1, 2, 3, 4, or 5 hydrogen bond donors. In certain embodiments,the compound has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hydrogen bondacceptors.

In another aspect, provided are pharmaceutical compositions comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and optionally a pharmaceutically acceptable excipient. Thepharmaceutical composition may be useful in treating proliferativediseases, such as cancer.

In yet another aspect, provided are methods of treating a conditionassociated with aberrant activity of a kinase, e.g., a protein kinase,the method comprising administering a compound of Formula (I), or apharmaceutical composition thereof, to a subject in need thereof in anamount sufficient to reduce kinase activity. In certain embodiments, thecompound reduces kinase activity by targeted degradation of the proteinkinase. In certain embodiments, the compound reduces kinase activity byinducing unfolding of the protein kinase. In certain embodiments, thecompound reduces kinase activity by covalently binding to the proteinkinase. In certain embodiments, the compound reduces kinase activity bynon-covalently binding to the protein kinase. In certain embodiments,the condition being treated is a proliferative disorder. In certainembodiments, the proliferative disorder is cancer.

The details of one or more embodiments of the invention are set forth inthe accompanying Figures, the Detailed Description, and the Examples.Other features, objects, and advantages of the invention will beapparent from the description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the general hydrophobic tagging induced degradationstrategy.

FIG. 2 depicts the results of a Invitrogen LanthaScreen™ Eu kinasebinding assay of TX2-112-1, TX2-113-1, TX2-114-1, TX2-120-1, andTX2-121-1 (depicted in Table 1).

FIG. 3 depicts results of a CellTiter-Glo® Luminescent Assay(anti-proliferation assay) of TX2-112-1, TX2-113-1, TX2-114-1,TX2-120-1, and TX2-121-1 (depicted in Table 1).

FIGS. 4A and 4B depict electrophoretic gel image (SDS-PAGE) results ofcompounds TX2-112-1, TX2-113-1, TX2-114-1, TX2-120-1, and TX2-121-1(FIG. 4A) and SML-11-124-1 and TX2-126-1 (FIG. 4B) immunoblotted againstvarious antibodies; line 1: ErbB3 antibody; line 2: Phospho-Akt (Ser473)antibody; line 3: p44/42 MAPK (p-Erk1/2) antibody; line 4: T-Aktantibody; and line 5: Phospho-p44/42 MAPK (T-Erk1/2) (Thr202/Thr204)antibody.

DEFINITIONS Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer.“Racemic” refers to a compound in which the percent by weight of oneenantiomer is equal to the percent by weight of the other enantiomer.

The terms “enantiomerically enriched,” “enantiomerically pure” and“non-racemic,” as used interchangeably herein, refer to a compound inwhich the percent by weight of one enantiomer is greater than the amountof that one enantiomer compared to a control mixture of the racemiccomposition (e.g., greater than 1:1 by weight). For example, anenantiomerically enriched enantiomer, means a compound having greaterthan 50% by weight of one enantiomer relative to the other enantiomer,e.g., at least 75% by weight, or at least 80% by weight. In someembodiments, the enrichment can be much greater than 80% by weight,providing a “substantially enantiomerically enriched,” “substantiallyenantiomerically pure” or a “substantially non-racemic” compound, whichrefers to a compound with at least 85% by weight of one enantiomerrelative to other enantiomer, e.g., at least 90% by weight, or at least95% by weight.

Enantiomers can be isolated from mixtures by methods known to thoseskilled in the art, including chiral high pressure liquid chromatography(HPLC) and the formation and crystallization of chiral salts; orpreferred enantiomers can be prepared by asymmetric syntheses. See, forexample, Jacques, et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725(1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, “alkyl” refers to a radical of a straight-chain orbranched saturated hydrocarbon group having from 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkylgroup has 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, analkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments,an alkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In someembodiments, an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). Insome embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), n-propyl(C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C), amyl (C₅), neopentyl(C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆).Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈)and the like. Unless otherwise specified, each instance of an alkylgroup is independently unsubstituted (an “unsubstituted alkyl”) orsubstituted (a “substituted alkyl”) with one or more substituents. Incertain embodiments, the alkyl group is an unsubstituted C₁₋₁₀ alkyl(e.g., —CH₃). In certain embodiments, the alkyl group is a substitutedC₁₋₁₀ alkyl.

As used herein, “haloalkyl” is a substituted alkyl group as definedherein wherein one or more of the hydrogen atoms are independentlyreplaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.“Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl groupwherein all of the hydrogen atoms are independently replaced by ahalogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, thehaloalkyl moiety has 1 to 8 carbon atoms (“C₁₋₈ haloalkyl”). In someembodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C₁₋₆haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbonatoms (“C₁₋₄ haloalkyl”). In some embodiments, the haloalkyl moiety has1 to 3 carbon atoms (“C₁₋₃ haloalkyl”). In some embodiments, thehaloalkyl moiety has 1 to 2 carbon atoms (“C₁₋₂ haloalkyl”). In someembodiments, all of the haloalkyl hydrogen atoms are replaced withfluoro to provide a perfluoroalkyl group. In some embodiments, all ofthe haloalkyl hydrogen atoms are replaced with chloro to provide a“perchloroalkyl” group. Examples of haloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl, and the like.

As used herein, “heteroalkyl” refers to an alkyl group as defined hereinwhich further includes at least one heteroatom (e.g., 1, 2, 3, or 4heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e.,inserted between adjacent carbon atoms of) and/or placed at one or moreterminal position(s) of the parent chain. In certain embodiments, aheteroalkyl group refers to a saturated group having from 1 to 10 carbonatoms and 1, 2, 3, or 4 heteroatoms within the parent chain(“heteroC₁₋₁₀ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatomswithin the parent chain (“heteroC₁₋₉ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1,2, 3, or 4 heteroatoms within the parent chain (“heteroC₁₋₈ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 7carbon atoms and 1, 2, 3, or 4 heteroatoms within the parent chain(“heteroC₁₋₇ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatomswithin the parent chain (“heteroC₁₋₆ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC₁₋₅ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 4carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC₁₋₄alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 3 carbon atoms and 1 heteroatom within the parent chain(“heteroC₁₋₃ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 2 carbon atoms and 1 heteroatom within theparent chain (“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 1 carbon atom and 1 heteroatom(“heteroC₁ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms withinthe parent chain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, eachinstance of a heteroalkyl group is independently unsubstituted (an“unsubstituted heteroalkyl”) or substituted (a “substitutedheteroalkyl”) with one or more substituents. In certain embodiments, theheteroalkyl group is an unsubstituted heteroC₁₋₁₀ alkyl. In certainembodiments, the heteroalkyl group is a substituted heteroC₁₋₁₀ alkyl.

As used herein, “alkenyl” refers to a radical of a straight-chain orbranched hydrocarbon group having from 2 to 10 carbon atoms and one ormore double bonds (e.g., 1, 2, 3, or 4 double bonds) and no triplebonds. In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently unsubstituted (an“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) withone or more substituents. In certain embodiments, the alkenyl group isan unsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenylgroup is a substituted C₂₋₁₀ alkenyl.

As used herein, “heteroalkenyl” refers to an alkenyl group as definedherein which further includes at least one heteroatom (e.g., 1, 2, 3, or4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e.,inserted between adjacent carbon atoms of) and/or placed at one or moreterminal position(s) of the parent chain. In certain embodiments, aheteroalkenyl group refers to a group having from 2 to 10 carbon atoms,at least one double bond, and 1, 2, 3, or 4 heteroatoms within theparent chain (“heteroC₂₋₁₀ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 9 carbon atoms at least one double bond,and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC₂₋₉alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbonatoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms withinthe parent chain (“heteroC₂₋₈ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 7 carbon atoms, at least one double bond,and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC₂₋₇alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbonatoms, at least one double bond, and 1, 2, or 3 heteroatoms within theparent chain (“heteroC₂₋₆ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 5 carbon atoms, at least one double bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₅ alkenyl”).In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, atleast one double bond, and 1 or 2 heteroatoms within the parent chain(“heteroC₂₋₄ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 3 carbon atoms, at least one double bond, and 1 heteroatom within theparent chain (“heteroC₂₋₃ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₆ alkenyl”).Unless otherwise specified, each instance of a heteroalkenyl group isindependently unsubstituted (an “unsubstituted heteroalkenyl”) orsubstituted (a “substituted heteroalkenyl”) with one or moresubstituents. In certain embodiments, the heteroalkenyl group is anunsubstituted heteroC₂₋₁₀ alkenyl. In certain embodiments, theheteroalkenyl group is a substituted heteroC₂₋₁₀ alkenyl.

As used herein, “alkynyl” refers to a radical of a straight-chain orbranched hydrocarbon group having from 2 to 10 carbon atoms and one ormore triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally oneor more double bonds (e.g., 1, 2, 3, or 4 double bonds) (“C₂₋₁₀alkynyl”). An alkynyl group that has one or more triple bonds and one ormore double bonds is also referred to as an “ene-yene” group. In someembodiments, an alkynyl group has 2 to 9 carbon atoms (“C₂₋₉ alkynyl”).In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C₂₋₈alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms(“C₂₋₇ alkynyl”). In some embodiments, an alkynyl group has 2 to 6carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, an alkynyl group has2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In some embodiments, an alkynylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, analkynyl group has 2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In someembodiments, an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The oneor more carbon-carbon triple bonds can be internal (such as in2-butynyl) or terminal (such as in 1-butynyl). Examples of C₂₋₄ alkynylgroups include, without limitation, ethynyl (C₂), 1-propynyl (C₃),2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examplesof C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkynyl groups aswell as pentynyl (C₅), hexynyl (C₆), and the like. Additional examplesof alkynyl include heptynyl (C₇), octynyl (C₈), and the like. Unlessotherwise specified, each instance of an alkynyl group is independentlyunsubstituted (an “unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents. In certainembodiments, the alkynyl group is an unsubstituted C₂₋₁₀ alkynyl. Incertain embodiments, the alkynyl group is a substituted C₂₋₁₀ alkynyl.

As used herein, “heteroalkynyl” refers to an alkynyl group as definedherein which further includes at least one heteroatom (e.g., 1, 2, 3, or4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e.,inserted between adjacent carbon atoms of) and/or placed at one or moreterminal position(s) of the parent chain. In certain embodiments, aheteroalkynyl group refers to a group having from 2 to 10 carbon atoms,at least one triple bond, and 1, 2, 3, or 4 heteroatoms within theparent chain (“heteroC₂₋₁₀ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond,and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC₂₋₉alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbonatoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms withinthe parent chain (“heteroC₂₋₈ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond,and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC₂₋₇alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbonatoms, at least one triple bond, and 1, 2, or 3 heteroatoms within theparent chain (“heteroC₂₋₆ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₅ alkynyl”).In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, atleast one triple bond, and 1 or 2 heteroatoms within the parent chain(“heteroC₂₋₄ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 3 carbon atoms, at least one triple bond, and 1 heteroatom within theparent chain (“heteroC₂₋₃ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₆ alkynyl”).Unless otherwise specified, each instance of a heteroalkynyl group isindependently unsubstituted (an “unsubstituted heteroalkynyl”) orsubstituted (a “substituted heteroalkynyl”) with one or moresubstituents. In certain embodiments, the heteroalkynyl group is anunsubstituted heteroC₂₋₁₀ alkynyl. In certain embodiments, theheteroalkynyl group is a substituted heteroC₂₋₁₀ alkynyl.

As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbonatoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 9 ring carbon atoms (“C₃₋₉ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C₃₋₈carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ringcarbon atoms (“C₃₋₇ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include, withoutlimitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄),cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl(C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. ExemplaryC₃₋₈ carbocyclyl groups include, without limitation, the aforementionedC₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈),cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl(C₈), and the like. Exemplary C₃₋₁₀ carbocyclyl groups include, withoutlimitation, the aforementioned C₃₋₈ carbocyclyl groups as well ascyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl(C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀),spiro[4.5]decanyl (C₁₀), and the like. In certain embodiments, thecarbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) orpolycyclic (e.g., containing a fused, bridged or spiro-fused ring systemsuch as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system(“tricyclic carbocyclyl”)) and can be saturated or can contain one ormore carbon-carbon double or triple bonds. Exemplary fused bicyclicsystems include, but are not limited to, decalin (cis or trans decalin).Exemplary fused tricyclic systems include, but are not limited to,fluorenyl. Exemplary spiro-fused bicyclic systems include, but are notlimited to, spiropentane. Exemplary bridged bicyclic systems include,but are not limited to, norbornane, norbornene, bicyclo[2.2.2]octane,bicyclo[2.2.2]oct-2-ene, bicyclo[3.2.1]octane, andbicyclo[2.2.1]heptan-2-one. Exemplary bridged tricyclic systems include,but are not limited to adamantane. “Carbocyclyl” includes ring systemswherein the carbocyclyl ring, as defined above, is fused with one ormore aryl or heteroaryl groups wherein the point of attachment is on thecarbocyclyl ring, and in such instances, the number of carbons continueto designate the number of carbons in the carbocyclic ring system.Unless otherwise specified, each instance of a carbocyclyl group isindependently unsubstituted (an “unsubstituted carbocyclyl”) orsubstituted (a “substituted carbocyclyl”) with one or more substituents.In certain embodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₄ carbocyclyl.

“Carbocyclylalkyl” is a subset of “alkyl” and refers to an alkyl group,as defined herein, substituted by an carbocyclyl group, as definedherein, wherein the point of attachment is on the alkyl moiety.

As used herein, “heterocyclyl” or “heterocyclic” refers to a radical ofa 3- to 14-membered non-aromatic ring system having ring carbon atomsand 1 to 4 ring heteroatoms, wherein each heteroatom is independentlyselected from nitrogen, oxygen, and sulfur (“3-14 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) ortricyclic system (“tricyclic heterocyclyl”)), and can be saturated orcan contain one or more carbon-carbon double or triple bonds.Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or both rings. In certain embodiments, the heterocyclyl group iseither monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g.,containing a fused, bridged or spiro-fused ring system such as abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”)) and can be saturated or can contain one ormore carbon-carbon double or triple bonds. “Heterocyclyl” also includesring systems wherein the heterocyclyl ring, as defined above, is fusedwith one or more carbocyclyl groups wherein the point of attachment iseither on the carbocyclyl or heterocyclyl ring, or ring systems whereinthe heterocyclyl ring, as defined above, is fused with one or more arylor heteroaryl groups, wherein the point of attachment is on theheterocyclyl ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclylring system. Unless otherwise specified, each instance of heterocyclylis independently unsubstituted (an “unsubstituted heterocyclyl”) orsubstituted (a “substituted heterocyclyl”) with one or moresubstituents. In certain embodiments, the heterocyclyl group is anunsubstituted 3-14 membered heterocyclyl. In certain embodiments, theheterocyclyl group is a substituted 3-14 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing 1 heteroatom include, withoutlimitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyl groups containing 2 heteroatomsinclude, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl.Exemplary 5-membered heterocyclyl groups containing 3 heteroatomsinclude, without limitation, triazolinyl, oxadiazolinyl, andthiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1heteroatom include, without limitation, piperidinyl, tetrahydropyranyl,dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, piperazinyl,morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclylgroups containing 2 heteroatoms include, without limitation,triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1heteroatom include, without limitation, azepanyl, oxepanyl andthiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

“Heterocyclylalkyl” is a subset of “alkyl” and refers to an alkyl group,as defined herein, substituted by an heterocyclyl group, as definedherein, wherein the point of attachment is on the alkyl moiety.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 n electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracenyl). “Aryl” also includes ring systemswherein the aryl ring, as defined above, is fused with one or morecarbocyclyl or heterocyclyl groups wherein the radical or point ofattachment is on the aryl ring, and in such instances, the number ofcarbon atoms continue to designate the number of carbon atoms in thearyl ring system. Unless otherwise specified, each instance of an arylgroup is independently unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is a substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl group, asdefined herein, substituted by an aryl group, as defined herein, whereinthe point of attachment is on the alkyl moiety.

As used herein, “heteroaryl” refers to a radical of a 5-14 memberedmonocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ringsystem (e.g., having 6, 10, or 14 π electrons shared in a cyclic array)having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-14 membered heteroaryl”). Inheteroaryl groups that contain one or more nitrogen atoms, the point ofattachment can be a carbon or nitrogen atom, as valency permits.Heteroaryl polycyclic ring systems can include one or more heteroatomsin one or both rings. “Heteroaryl” includes ring systems wherein theheteroaryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the point of attachment is on theheteroaryl ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heteroaryl ringsystem. “Heteroaryl” also includes ring systems wherein the heteroarylring, as defined above, is fused with one or more aryl groups whereinthe point of attachment is either on the aryl or heteroaryl ring, and insuch instances, the number of ring members designates the number of ringmembers in the fused polycyclic (aryl/heteroaryl) ring system.Polycyclic heteroaryl groups wherein one ring does not contain aheteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) thepoint of attachment can be on either ring, i.e., either the ring bearinga heteroatom (e.g., 2-indolyl) or the ring that does not contain aheteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-14membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include,without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary5-membered heteroaryl groups containing 2 heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing 3heteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4heteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, andpyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing 1heteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplarytricyclic heteroaryl groups include, without limitation,phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl,phenoxazinyl and phenazinyl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group, asdefined herein, substituted by a heteroaryl group, as defined herein,wherein the point of attachment is on the alkyl moiety.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl moieties) as herein defined.

As used herein, the term “saturated” refers to a ring moiety that doesnot contain a double or triple bond, i.e., the ring contains all singlebonds.

Affixing the suffix “-ene” to a group indicates the group is a divalentmoiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene isthe divalent moiety of alkenyl, alkynylene is the divalent moiety ofalkynyl, heteroalkylene is the divalent moiety of heteroalkyl,heteroalkenylene is the divalent moiety of heteroalkenyl,heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclyleneis the divalent moiety of carbocyclyl, heterocyclylene is the divalentmoiety of heterocyclyl, arylene is the divalent moiety of aryl, andheteroarylene is the divalent moiety of heteroaryl.

As understood from the above, alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl groups, as defined herein, are, in certain embodiments,optionally substituted. Optionally substituted refers to a group whichmay be substituted or unsubstituted (e.g., “substituted” or“unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl,“substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” heteroalkyl, “substituted” or “unsubstituted”heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted”, whether preceded by the term “optionally” or not, meansthat at least one hydrogen present on a group (e.g., a carbon ornitrogen atom) is replaced with a permissible substituent, e.g., asubstituent which upon substitution results in a stable compound, e.g.,a compound which does not spontaneously undergo transformation such asby rearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group has a substituent at one ormore substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. The term “substituted” iscontemplated to include substitution with all permissible substituentsof organic compounds, any of the substituents described herein thatresults in the formation of a stable compound. The present inventioncontemplates any and all such combinations in order to arrive at astable compound. For purposes of this invention, heteroatoms such asnitrogen may have hydrogen substituents and/or any suitable substituentas described herein which satisfy the valencies of the heteroatoms andresults in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀ heteroalkyl, C₂₋₁₀ heteroalkenyl, C₂₋₁₀heteroalkynyl,C₃₋₁₄ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ heteroalkyl,C₂₋₁₀ heteroalkenyl, C₂₋₁₀heteroalkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(aa) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R, —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀ heteroalkyl, C₂₋₁₀ heteroalkenyl, C₂₋₁₀heteroalkynyl,C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀heteroalkyl, C₂₋₁₀ heteroalkenyl, C₂₋₁₀heteroalkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(cc) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —C, —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ heteroalkyl, C₂₋₆heteroalkenyl, C₂₋₆heteroalkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminalR^(dd) substituents can be joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ heteroalkyl, C₂₋₆heteroalkenyl, C₂₋₆heteroalkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ heteroalkyl,C₂₋₆ heteroalkenyl, C₂₋₆heteroalkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆heteroalkyl, C₂₋₆ heteroalkenyl, C₂₋₆heteroalkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X is a counterion.

As used herein, the term “halo” or “halogen” refers to fluorine (fluoro,—F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

As used herein, a “counterion” is a negatively charged group associatedwith a positively charged quarternary amine in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

As used herein, the term “hydroxyl” or “hydroxy” refers to the group—OH. The term “substituted hydroxyl” or “substituted hydroxyl,” byextension, refers to a hydroxyl group wherein the oxygen atom directlyattached to the parent molecule is substituted with a group other thanhydrogen, and includes groups selected from —OR^(aa), —ON(R^(bb))₂,—OC(═O)SR^(aa), OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂,—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂,—OS(═O)R^(aa), —OSO₂R^(aa), —OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃,—OP(═O)₂R^(aa), —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂,and —OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein.

As used herein, the term “thiol” or “thio” refers to the group —SH. Theterm “substituted thiol” or “substituted thio,” by extension, refers toa thiol group wherein the sulfur atom directly attached to the parentmolecule is substituted with a group other than hydrogen, and includesgroups selected from —SR^(aa), —S═SR^(cc), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —SC(═O)OR^(aa), and —SC(═O)R^(aa), wherein R^(aa) andR^(cc) are as defined herein.

As used herein, the term, “amino” refers to the group —NH₂. The term“substituted amino,” by extension, refers to a monosubstituted amino, adisubstituted amino, or a trisubstituted amino, as defined herein. Incertain embodiments, the “substituted amino” is a monosubstituted aminoor a disubstituted amino group.

As used herein, the term “monosubstituted amino” refers to an aminogroup wherein the nitrogen atom directly attached to the parent moleculeis substituted with one hydrogen and one group other than hydrogen, andincludes groups selected from —NH(R^(bb)), —NHC(═O)R^(aa), NHCO₂R^(aa),—NHC(═O)N(R^(bb))₂, —NHC(═NR^(bb))N(R^(bb))₂, —NHSO₂R^(aa),—NHP(═O)(OR^(cc))₂, and —NHP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb) andR^(cc) are as defined herein, and wherein R^(bb) of the group—NH(R^(bb)) is not hydrogen.

As used herein, the term “disubstituted amino” refers to an amino groupwherein the nitrogen atom directly attached to the parent molecule issubstituted with two groups other than hydrogen, and includes groupsselected from —N(R^(bb))₂, —NR^(bb) C(═O)R^(aa), —NR^(bb)CO₂R^(aa),NR^(bb)C(═O)N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,—NR^(bb)SO₂R^(aa), —NR^(bb)P(═O)(OR^(cc))₂, and —NR^(bb)P(═O)(NR^(bb))₂,wherein R^(aa), R^(bb), and R^(cc) are as defined herein, with theproviso that the nitrogen atom directly attached to the parent moleculeis not substituted with hydrogen.

As used herein, the term “trisubstituted amino” refers to an amino groupwherein the nitrogen atom directly attached to the parent molecule issubstituted with three groups, and includes groups selected from—N(R^(bb))₃ and —N(R^(bb))₃ ⁺X⁻, wherein R^(bb) and X⁻ are as definedherein.

As used herein, the term “oxo” refers to the group ═O, and the term“thiooxo” refers to the group ═S.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀heteroalkyl, C₂₋₁₀ heteroalkenyl, C₂₋₁₀ heteroalkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on the nitrogen atom isan nitrogen protecting group (also referred to herein as an “aminoprotecting group”). Nitrogen protecting groups include, but are notlimited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R, —SO₂R, —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀heteroalkyl, C₂₋₁₀ heteroalkenyl, C₂₋₁₀ heteroalkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined herein. Nitrogen protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamante, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R, —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR,—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, o-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, o-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate, Ms), benzylsulfonate,benzenesulfonate (besylate, Bs), and toluenesulfonate (tosylate, Ts).

In certain embodiments, the substituent present on an sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

As used herein, a “leaving group” is an art-understood term referring toa molecular fragment that departs with a pair of electrons inheterolytic bond cleavage, wherein the molecular fragment is an anion orneutral molecule. See, for example, Smith, March Advanced OrganicChemistry 6th ed. (501-502). Exemplary leaving groups include, but arenot limited to, halo (e.g., chloro, bromo, iodo) and sulfonylsubstituted hydroxyl groups (e.g., tosyl, mesyl, besyl).

Other Definitions

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or othernon-human animals, for example mammals (e.g., primates (e.g., cynomolgusmonkeys, rhesus monkeys); commercially relevant mammals such as cattle,pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g.,commercially relevant birds such as chickens, ducks, geese, and/orturkeys), reptiles, amphibians, and fish. In certain embodiments, thenon-human animal is a mammal. The non-human animal may be a male orfemale and at any stage of development. A non-human animal may be atransgenic animal.

A “condition,” “disease,” and “disorder” are used interchangeablyherein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent. In the context of treatment of conditions associated withabherant Her3 activity, in certain embodiments, a therapeuticallyeffective amount is an amount sufficient to reduce Her3 activity, reduceHer3 protein levels, and/or inhibit cell proliferation.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

As used herein an “inhibitor” refers to the ability of a compound toreduce (e.g., slow, halt) or prevent activity of a particular biologicalprocess (kinase activity) in a cell relative to vehicle.

As used herein, use of the phrase “at least one instance” refers to 1,2, 3, 4, or more instances, but also encompasses a range, e.g., forexample, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to3, or from 3 to 4 instances, inclusive.

“Kinase.” A kinase is a type of enzyme that transfers phosphate groupsfrom high energy donor molecules, such as ATP, to specific substrates,referred to as phosphorylation. Kinases are part of the larger family ofphosphotransferases. One of the largest groups of kinases are proteinkinases, which act on and modify the activity of specific proteins.Kinases are used extensively to transmit signals and control complexprocesses in cells. Various other kinases act on small molecules such aslipids, carbohydrates, amino acids, and nucleotides, either forsignaling or to prime them for metabolic pathways. Kinases are oftennamed after their substrates. More than 500 different protein kinaseshave been identified in humans. These exemplary human protein kinasesinclude, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1,AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa,ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC,AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B,BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a,CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1,CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2, CDK3,CDK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps, CDK9,CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps, CHED, CHK1, CHK2, CHK2ps1,CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d, CK1e, CK1g1,CK1g2, CK1g2ps, CK1g3, CK2a1, CK2a1-rs, CK2a2, CLIK1, CLIK1L, CLK1,CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT, CRIK, CRK7, CSK, CTK, CYGD, CYGF,DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK1,DMPK2, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EGFR, EphA1,EphA10, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2,EphB3, EphB4, EphB6, Erk1, Erk2, Erk3, Erk3ps1, Erk3ps2, Erk3ps3,Erk3ps4, Erk4, Erk5, Erk7, FAK, FER, FERps, FES, FGFR1, FGFR2, FGFR3,FGFR4, FGR, FLT1, FLT1ps, FLT3, FLT4, FMS, FRK, Fused, FYN, GAK, GCK,GCN2, GCN22, GPRK4, GPRK5, GPRK6, GPRK6ps, GPRK7, GSK3A, GSK3B, Haspin,HCK, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, HH498, HIPK1, HIPK2, HIPK3,HIPK4, HPK1, HRI, HRIps, HSER, HUNK, ICK, IGF1R, IKKa, IKKb, IKKe, ILK,INSR, IRAK1, IRAK2, IRAK3, IRAK4, IRE1, IRE2, IRR, ITK, JAK1, JAK12,JAK2, JAK22, JAK3, JAK32, JNK1, JNK2, JNK3, KDR, KHS1, KHS2, KIS, KIT,KSGCps, KSR1, KSR2, LATS1, LATS2, LCK, LIMK1, LIMK2, LIMK2ps, LKB1,LMR1, LMR2, LMR3, LOK, LRRK1, LRRK2, LTK, LYN, LZK, MAK, MAP2K1,MAP2K1ps, MAP2K2, MAP2K2ps, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7,MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8,MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPKAPKps1, MARK1, MARK2, MARK3, MARK4,MARKps01, MARKps02, MARKps03, MARKps04, MARKps05, MARKps07, MARKps08,MARKps09, MARKps10, MARKps11, MARKps12, MARKps13, MARKps15, MARKps16,MARKps17, MARKps18, MARKps19, MARKps20, MARKps21, MARKps22, MARKps23,MARKps24, MARKps25, MARKps26, MARKps27, MARKps28, MARKps29, MARKps30,MAST1, MAST2, MAST3, MAST4, MASTL, MELK, MER, MET, MISR2, MLK1, MLK2,MLK3, MLK4, MLKL, MNK1, MNK1ps, MNK2, MOK, MOS, MPSK1, MPSK1ps, MRCKa,MRCKb, MRCKps, MSK1, MSK12, MSK2, MSK22, MSSK1, MST1, MST2, MST3,MST3ps, MST4, MUSK, MYO3A, MYO3B, MYT1, NDR1, NDR2, NEK1, NEK10, NEK11,NEK2, NEK2ps1, NEK2ps2, NEK2ps3, NEK3, NEK4, NEK4ps, NEK5, NEK6, NEK7,NEK8, NEK9, NIK, NIM1, NLK, NRBP1, NRBP2, NuaK1, NuaK2, Obscn, Obscn2,OSR1, p38a, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kps1, p70S6Kps2,PAK1, PAK2, PAK2ps, PAK3, PAK4, PAK5, PAK6, PASK, PBK, PCTAIRE1,PCTAIRE2, PCTAIRE3, PDGFRa, PDGFRb, PDK1, PEK, PFTAIRE1, PFTAIRE2,PHKg1, PHKg1ps1, PHKg1ps2, PHKg1ps3, PHKg2, PIK3R4, PIM1, PIM2, PIM3,PINK1, PITSLRE, PKACa, PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh,PKCi, PKCips, PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2,PKN3, PKR, PLK1, PLK1ps1, PLK1ps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY,PRP4, PRP4ps, PRPK, PSKH1, PSKH1ps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps,RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2,ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2,RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps,SgK069, SgK071, SgK085, SgK110, SgK196, SGK2, SgK223, SgK269, SgK288,SGK3, SgK307, SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496,SIK, skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM, SRPK1,SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6, STLK6ps1,STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC, TESK1,TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2, TLK2ps1, TLK2ps2,TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC, TSSK1, TSSK2,TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN, TXK, TYK2,TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1, VRK2,VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1, Wee1ps2, Wnk1, Wnk2, Wnk3,Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1/HGK,ZC2/TNIK, ZC3/MINK, ZC4/NRK. In certain embodiments, the kinase isHER3/ErbB3 (“Her3 kinase”).

As used herein, “hydrophobic,” in the context of a “hydrophobic” group—R^(H), refers to a group —R^(H) which comprises zero hydrogen bonddonors (e.g., zero —NH, —OH, and/or —SH groups) and optionally zerohydrogen bond acceptors (e.g., O, N, and/or S atoms). In certainembodiments, the hydrophobic group —R^(H) comprises zero hydrogen bonddonors and zero hydrogen bond acceptors. For example, in certainembodiments, the hydrophobic group —R^(H) is an unsubstitutedhydrocarbon (carbocyclylalkyl, carbocyclyl, aralkyl, or aryl) group,i.e., comprising only carbon and hydrogen. In certain embodiments, thehydrophobic group —R^(H) comprises at least 6 carbon atoms, e.g.,between 6 and 50 carbon atoms, between 6 and 40 carbon atoms, between 6and 30 carbon atoms, between 6 and 20 carbon atoms, or between 6 and 15carbon atoms. In certain embodiments, the hydrophobic group —R^(H)comprises 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20carbon atoms.

A “small organic molecule,” (M) as used herein, refers to an alkyl,alkenyl, alknyl, aryl, heteroaryl, carbocyclic, or heterocyclic moiety,as defined herein, comprising carbon and hydrogen, and optionallycomprising one or more heteroatoms as a part of the molecule (in thecase of heteroaryl and heterocyclic groups) and/or attached to themolecule selected from oxygen, nitrogen, sulfur, phosphorus, boron,silicon, and selenium.

“Molecular weights.” The molecular weight of said small organic molecule(M), in the absence of the group -L¹-R^(H) (such that the group-L¹-R^(H) is replaced with hydrogen to provide M-H), is between about100 g/mol and about 800 g/mol, inclusive, e.g., between about 100 andabout 750 g/mol, between about 100 and about 700 g/mol, between about100 and about 650 g/mol, between about 100 and about 600 g/mol, betweenabout 100 and about 550 g/mol, between about 100 and about 500 g/mol,between about 100 and about 450 g/mol, between about 100 and about 400g/mol, between about 100 and about 350 g/mol, between about 100 andabout 300 g/mol, between about 100 and about 250 g/mol, between about100 and about 200 g/mol, between about 100 and about 150 g/mol, betweenabout 200 g/mol to about 800 g/mol, between about 200 g/mol to about 700g/mol, between about 200 g/mol to about 600 g/mol, between about 200g/mol to about 500 g/mol, between about 200 g/mol to about 400 g/mol,between about 200 g/mol to about 300 g/mol, between about 300 g/mol toabout 800 g/mol, between about 300 g/mol to about 700 g/mol, betweenabout 300 g/mol to about 600 g/mol, between about 300 g/mol to about 500g/mol, between about 300 g/mol to about 400 g/mol, between about 400g/mol to about 800 g/mol, between about 400 g/mol to about 700 g/mol,between about 400 g/mol to about 600 g/mol, between about 400 g/mol toabout 500 g/mol, or between about 400 g/mol to about 400 g/mol,inclusive.

The molecular weight of the group -L¹-R^(H) is, in certain embodiments,between about 50 g/mol and about 600 g/mol, inclusive, e.g., betweenabout 50 g/mol and about 500 g/mol, between about 100 g/mol and about500 g/mol, between about 100 g/mol and about 400 g/mol, between about100 g/mol and about 300 g/mol, between about 100 g/mol and about 200g/mol, between about 200 g/mol and about 400 g/mol, or between about 200g/mol and about 300 g/mol, inclusive.

The molecular weight of the hydrophobic group —R^(H) is, in certainembodiments, between about 100 g/mol and about 300 g/mol, inclusive,e.g., between about 100 g/mol and about 200 g/mol, between about 100g/mol and about 180 g/mol, between about 110 g/mol and about 180 g/mol,between about 120 g/mol and about 180 g/mol, or between about 130 g/moland about 180 g/mol, inclusive.

The total molecular weight of the compound of Formula (I), is thecumulative molecular weight of the small molecule (M) and group-L¹-R^(H). In certain embodiments, the total molecular weight of thecompound of Formula (I) is between about 200 g/mol to about 1000 g/mol,inclusive, e.g., between about 200 g/mol to about 900 g/mol, betweenabout 200 g/mol to about 800 g/mol, between about 200 g/mol to about 700g/mol, between about 200 g/mol to about 600 g/mol, between about 200g/mol to about 500 g/mol, between about 200 g/mol to about 400 g/mol,between about 200 g/mol to about 300 g/mol, between about 300 g/mol toabout 800 g/mol, between about 400 g/mol to about 1000 g/mol, betweenabout 400 g/mol to about 900 g/mol, between about 400 g/mol to about 800g/mol, between about 400 g/mol to about 700 g/mol, between about 400g/mol to about 600 g/mol, between about 400 g/mol to about 500 g/mol,between about 500 g/mol to about 1000 g/mol, between about 500 g/mol toabout 900 g/mol, between about 500 g/mol to about 800 g/mol, betweenabout 500 g/mol to about 700 g/mol, or between about 500 g/mol to about600 g/mol, inclusive.

For example, the molecular weight of the small molecule of Formula(II′), which is the small molecule as defined in Formula (II) in theabsence of the group -L¹-R^(H) (wherein -L¹-R^(H) is replaced withhydrogen to provide M-H):

is between about 251 g/mol and about 800 g/mol, inclusive. 251 g/mol isthe lowest molecular weight contemplated for this particular formula,wherein a and b are each 0, both instances of R^(B) are hydrogen, andRing A is unsubstituted cyclopropyl.

In certain embodiments, the molecular weight of the small molecule (M-H)of Formula (II′) is between about 251 g/mol to about 800 g/mol, betweenabout 251 g/mol to about 700 g/mol, between about 251 g/mol to about 600g/mol, between about 251 g/mol to about 500 g/mol, between about 251g/mol to about 400 g/mol, between about 300 g/mol to about 800 g/mol,between about 300 g/mol to about 700 g/mol, between about 300 g/mol toabout 600 g/mol, between about 300 g/mol to about 500 g/mol, betweenabout 300 g/mol to about 400 g/mol, between about 400 g/mol to about 800g/mol, between about 400 g/mol to about 700 g/mol, between about 400g/mol to about 600 g/mol, or between about 400 g/mol to about 500 g/mol,inclusive.

Furthermore, in the instance of the total molecular weight of a compoundof Formula (II), which is the cumulative molecular weight of the smallmolecule (M) and the group -L¹-R^(H), is, in certain embodiments,between about 351 g/mol and about 1000 g/mol, inclusive, e.g., betweenabout 400 g/mol to about 1000 g/mol, between about 400 g/mol to about900 g/mol, between about 400 g/mol to about 800 g/mol, between about 400g/mol to about 700 g/mol, between about 400 g/mol to about 600 g/mol,between about 400 g/mol to about 500 g/mol, between about 500 g/mol toabout 1000 g/mol, between about 500 g/mol to about 900 g/mol, betweenabout 500 g/mol to about 800 g/mol, between about 500 g/mol to about 700g/mol, or between about 500 g/mol to about 600 g/mol, inclusive.

Furthermore, in the instance of a compound of Formula (II), in certainembodiments, the molecular weight of the group -L¹-R^(H) provided inFormula (II) is between about 50 g/mol and about 400 g/mol, e.g.,between about 100 g/mol and about 400 g/mol, between about 100 g/mol andabout 300 g/mol, between about 100 g/mol and about 200 g/mol, betweenabout 200 g/mol and about 400 g/mol, or between about 200 g/mol andabout 300 g/mol, inclusive.

In certain embodiments, the total molecular weight of the compound ofFormula (II) is between about 500 g/mol to about 1000 g/mol, inclusive,and the molecular weight of the group -L¹-R^(H) provided in Formula (II)is between about 100 g/mol and about 400 g/mol, inclusive.

In certain embodiments, the total molecular weight of the compound ofFormula (II) is between about 500 g/mol to about 1000 g/mol, inclusive,and the molecular weight of the small molecule (M-H) of Formula (II′) isbetween about 400 g/mol to about 600 g/mol, inclusive.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As generally described herein, the present invention is based on thedevelopment of bifunctional compounds (i.e., a kinase binding smallmolecule tagged with a hydrophobic moiety) that can induce thedegradation of a kinase, e.g., a protein kinase, of interest. Thesebifunctional compounds possess a kinase recognition element that canbind either covalently or non-covalently and a ‘hydrophobic’ tag elementthat signals to the intracellular protein homeostasis machinery toinduce degradation of the targeted kinase.

Bifunctional compounds contemplated herein may be generally representedby Formula (I):

or a pharmaceutically acceptable salt thereof;wherein:

M represents a small organic molecule which binds to a kinase;

L¹ represents a linker selected from the group consisting of substitutedand unsubstituted alkylene, substituted and unsubstituted alkenylene,substituted and unsubstituted alkynylene, substituted and unsubstitutedheteroalkylene, substituted and unsubstituted heteroalkenylene,substituted and unsubstituted heteroalkynylene, substituted andunsubstituted heterocyclylene, substituted and unsubstitutedcarbocyclylene, substituted and unsubstituted arylene, substituted andunsubstituted heteroarylene, and combinations thereof; and

R^(H) represents a hydrophobic group selected from the group consistingof substituted and unsubstituted aryl, substituted and unsubstitutedheteroaryl, substituted and unsubstituted carbocyclyl, substituted andunsubstituted heterocyclyl, substituted and unsubstituted aralkyl,substituted and unsubstituted heteroarylalkyl, substituted andunsubstituted carbocycylalkyl, and substituted and unsubstitutedheterocyclylalkyl.

As described herein, M represents a small organic molecule which binds,covalently or non-covalently, to a particular kinase even when the group-L¹-R^(H) is absent, i.e., wherein the group -L¹-R^(H) is replaced, forexample, with hydrogen (M-H). In certain embodiments, the small organicmolecule (M or M-H) covalently binds the kinase. In certain embodiments,the small organic molecule (M or M-H) non-covalently binds the kinase.In certain embodiments, the non-covalent binding affinity of the smallorganic molecule (M or M-H) to the kinase is between about 0.1 nanomolarand 1000 nanomolar, inclusive, e.g., between about 1 nanomolar and 1000nanomolar, between about 10 nanomolar and 1000 nanomolar, between about100 nanomolar and 1000 nanomolar, between about 500 nanomolar and 1000nanomolar, between about 0.1 nanomolar and 500 nanomolar, between about0.1 nanomolar and 100 nanomolar, between about 0.1 nanomolar and 50nanomolar, inclusive.

In certain embodiments the kinase is a protein kinase. In certainembodiments the kinase is a human protein kinase. In certainembodiments, the human protein kinase is HER3/ErbB3 (“Her3 kinase”).

Linker L¹

As described herein, L¹ represents a linker selected from the groupconsisting of substituted and unsubstituted alkylene; substituted andunsubstituted alkenylene; substituted and unsubstituted alkynylene;substituted and unsubstituted heteroalkylene; substituted andunsubstituted heteroalkenylene; substituted and unsubstitutedheteroalkynylene; substituted and unsubstituted heterocyclylene;substituted and unsubstituted carbocyclylene; substituted andunsubstituted arylene; substituted and unsubstituted heteroarylene; andcombinations thereof.

As used herein, reference to a linker consisting of a combination refersto a linker comparing 1, 2, 3, 4 or more of the recited moieties. Forexample, the linker may consist of an alkylene attached to aheteroalkylene, which may be further optionally attached to anotheralkylene. As used herein “at least one instance” refers to 1, 2, 3, 4,or more instances of the recited moiety.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted alkylene, e.g., substituted orunsubstituted C₁₋₆alkylene, substituted or unsubstituted C₁₋₂alkylene,substituted or unsubstituted C₂₋₃alkylene, substituted or unsubstitutedC₃₋₄alkylene, substituted or unsubstituted C₄₋₅alkylene, substituted orunsubstituted C₅₋₆alkylene, substituted or unsubstituted C₃₋₆alkylene,or substituted or unsubstituted C₄₋₆alkylene. Exemplary alkylene groupsinclude unsubstituted alkylene groups such as methylene —CH₂—, ethylene—(CH₂)₂—, n-propylene —(CH₂)₃—, n-butylene —(CH₂)₄—, n-pentylene—(CH₂)₅—, and n-hexylene —(CH₂)₆—.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted alkenylene, e.g., substituted orunsubstituted C₂₋₆alkenylene, substituted or unsubstitutedC₂₋₃alkenylene, substituted or unsubstituted C₃₋₄alkenylene, substitutedor unsubstituted C₄₋₅alkenylene, or substituted or unsubstitutedC₅₋₆alkenylene.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted alkynylene, e.g., substituted orunsubstituted C₂₋₆alkynylene, substituted or unsubstitutedC₂₋₃alkynylene, substituted or unsubstituted C₃₋₄alkynylene, substitutedor unsubstituted C₄₋₅alkynylene, or substituted or unsubstitutedC₅₋₆alkynylene.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted heteroalkylene, e.g., substituted orunsubstituted heteroC₁₋₆alkylene, substituted or unsubstitutedheteroC₁₋₂alkylene, substituted or unsubstituted heteroC₂₋₃alkylene,substituted or unsubstituted heteroC₃₋₄alkylene, substituted orunsubstituted heteroC₄₋₅alkylene, or substituted or unsubstitutedheteroC₅₋₆alkylene. Exemplary heteroalkylene groups includeunsubstituted alkylene groups such as —(CH₂)₂—O(CH₂)₂—, —OCH₂—, —CH₂O—,—O(CH₂)₂—, —(CH₂)₂O—, —O(CH₂)₃—, —(CH₂)₃O—, —O(CH₂)₄—, —(CH₂)₄O—,—O(CH₂)₅—, —(CH₂)₅O—, —O(CH₂)₆—, and —O(CH₂)₆O—.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted heteroalkenylene, e.g., substituted orunsubstituted heteroC₂₋₆alkenylene, substituted or unsubstitutedheteroC₂₋₃alkenylene, substituted or unsubstituted heteroC₃₋₄alkenylene,substituted or unsubstituted heteroC₄₋₅alkenylene, or substituted orunsubstituted heteroC₅₋₆alkenylene.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted heteroalkynylene, e.g., substituted orunsubstituted heteroC₂₋₆alkynylene, substituted or unsubstitutedheteroC₂₋₃alkynylene, substituted or unsubstituted heteroC₃₋₄alkynylene,substituted or unsubstituted heteroC₄₋₅alkynylene, or substituted orunsubstituted heteroC₅₋₆alkynylene.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted carbocyclylene, e.g., substituted orunsubstituted C₃₋₆carbocyclylene, substituted or unsubstitutedC₃₋₄carbocyclylene, substituted or unsubstituted C₄₋₅ carbocyclylene, orsubstituted or unsubstituted C₅₋₆ carbocyclylene.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted heterocyclylene, e.g., substituted orunsubstituted C₃₋₆ heterocyclylene, substituted or unsubstituted C₃₋₄heterocyclylene, substituted or unsubstituted C₄₋₅ heterocyclylene, orsubstituted or unsubstituted C₅₋₆ heterocyclylene.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted arylene, e.g., substituted or unsubstitutedphenylene.

In certain embodiments, L¹ comprises at least one instance ofsubstituted or unsubstituted heteroarylene, e.g., substituted orunsubstituted 5- to 6-membered heteroarylene.

In certain embodiments, L¹ is a linker that contains an asymmetriccarbon/stereocenter, i.e., an sp³ hybridized carbon atom bearing 4different groups attached thereto. In certain embodiments, the compoundcomprising such an L¹ group is enantiomerically enriched orsubstantially enantiomerically enriched, as defined herein. However, incertain embodiments, the compound comprising such an L¹ group isracemic.

In certain embodiments, L¹ represents a linker consisting of acombination of one or more consecutive covalently bonded groups of theformulae:

wherein:

-   -   each instance of n is independently an integer between 1 to 10,        inclusive;    -   each instance of m is independently 0, 1, or 2;    -   each instance of Q is independently —NR^(W1)—;        —NR^(W1)—NR^(W1)—; —O—NR^(W1)—; —NR^(W1)—O—; —S—; or —O—;    -   each instance of W is independently O, S, or NR^(W1);

each instance of G₁ and G₂ are independently N or CH;

each instance of R^(W1) is independently hydrogen; substituted orunsubstituted alkyl; substituted or unsubstituted alkenyl; substitutedor unsubstituted alkynyl; substituted or unsubstituted carbocyclyl;substituted or unsubstituted heterocyclyl; substituted or unsubstitutedaryl; substituted or unsubstituted heteroaryl; a nitrogen protectinggroup if attached to a nitrogen atom, or an oxygen protecting group ifattached to an oxygen atom;

-   -   each instance of R^(W2) is independently hydrogen; substituted        or unsubstituted alkyl; substituted or unsubstituted alkenyl;        substituted or unsubstituted alkynyl; substituted or        unsubstituted carbocyclyl; substituted or unsubstituted        heterocyclyl; substituted or unsubstituted aryl; substituted or        unsubstituted heteroaryl; or two R^(W2) groups are joined to        form a 5-6 membered ring; and

each instance of R^(W3) is independently hydrogen; halogen; substitutedor unsubstituted alkyl; substituted or unsubstituted alkenyl;substituted or unsubstituted alkynyl; substituted or unsubstitutedcarbocyclyl; substituted or unsubstituted heterocyclyl; substituted orunsubstituted aryl; or substituted or unsubstituted heteroaryl, or twoR^(W3) groups are joined to form a 3-6 membered ring;

or R^(W1) and R^(W3) are joined to form a 5-6 membered heterocyclicring.

As described herein, n of any of the below formulae is independently aninteger between 1 to 10, inclusive, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or10:

In certain embodiments, n is 1, 2, or 3. In certain embodiments, eachinstance of R^(W3) is independently hydrogen; halogen; or substituted orunsubstituted alkyl (e.g., methyl).

As described herein, m of any of the below formulae is independently 0,1, or 2, and G₁ and G₂ are independently N or CH:

In certain embodiments, m is 0, and R^(W3) is absent. In certainembodiments, m is 1. In certain embodiments, m is 2. In certainembodiments, G₁ is N. In certain embodiments, G₁ is CH. In certainembodiments, G₂ is N. In certain embodiments, G₂ is CH. In certainembodiments, G₁ is N and G₂ is CH. In certain embodiments, G₁ is CH andG₂ is CH. In certain embodiments, G₁ is N and G₂ is N. In certainembodiments, G₁ is CH and G₂ is N. In certain embodiments, each instanceof R^(W3) is independently hydrogen; halogen; or substituted orunsubstituted alkyl (e.g., methyl).

As described herein, each instance of Q of any of the below formulae isindependently —NR^(W1)—; —NR^(W1)—NR^(W1)—; —O—NR^(W1)—; —NR^(W1)—O—;—S—; or —O—, and each instance of W of any of the below formulae isindependently O, S, or NR^(W1):

In certain embodiments, Q is —NR^(W1)—. In certain embodiments, Q is—NR^(W1)—NR^(W1)—. In certain embodiments, Q is —O—NR^(W1)—. In certainembodiments, Q is —NR^(W1)—O—. In certain embodiments, Q is —S—. Incertain embodiments, Q is —O—. In certain embodiments, W is O. Incertain embodiments, W is S. In certain embodiments, W is NR^(W1). Incertain embodiments, W is O and Q is independently —S—, —NR^(W1)—, or—O—. In certain embodiments, R^(W1) is not hydrogen. In certainembodiments, R^(W2) is hydrogen or substituted or unsubstituted alkyl(e.g., methyl).

As described herein, each instance of R^(W1) is independently hydrogen;substituted or unsubstituted alkyl; substituted or unsubstitutedalkenyl; substituted or unsubstituted alkynyl; substituted orunsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl; a nitrogen protecting group if attached to a nitrogen atom,or an oxygen protecting group if attached to an oxygen atom. In any ofthe above formulae, as described herein, each instance of R^(W1) isindependently hydrogen; substituted or unsubstituted alkyl (e.g.,methyl); a nitrogen protecting group if attached to a nitrogen atom, oran oxygen protecting group if attached to an oxygen atom.

As described herein, each instance of R^(W2) is independently hydrogen;substituted or unsubstituted alkyl; substituted or unsubstitutedalkenyl; substituted or unsubstituted alkynyl; substituted orunsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl; or two R^(W2) groups are joined to form a 5-6 membered ring.In any of the above formulae, as described herein, each instance ofR^(W2) is independently hydrogen or substituted or unsubstituted alkyl(e.g., methyl).

As described herein, each instance of R^(W3) is independently hydrogen;halogen; substituted or unsubstituted alkyl; substituted orunsubstituted alkenyl; substituted or unsubstituted alkynyl; substitutedor unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; or substituted or unsubstitutedheteroaryl, or two R^(W3) groups are joined to form a 3-6 membered ring.In any of the above formulae, as described herein, each instance ofR^(W3) is independently hydrogen; halogen; substituted or unsubstitutedalkyl (e.g., methyl).

In certain embodiments, L¹ represents a linker consisting of acombination of one or more consecutively covalently bonded groups of theformula:

In certain embodiments, L¹ represents a linker consisting of acombination of 1 to 20 consecutive covalently bonded groups of the abovedescribed formulae, e.g., 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 8to 20, 9 to 20, 10 to 20, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, or 2to 5 groups, inclusive. In certain embodiments, L¹ represents a linkerconsisting of a combination of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 20 consecutive covalently bonded groupsof the above described formulae.

In certain embodiments, L¹ represents a linker 4 to 20 consecutivecovalently bonded atoms in length, inclusive, e.g., 4 to 19, 4 to 18, 4to 17, 4 to 16, 4 to 15, 4 to 14, 4 to 13, 4 to 12, 4 to 11, 4 to 10, 4to 9, 4 to 8, 4 to 7, 4 to 6, or 5 to 11 consecutive covalently bondedatoms in length, inclusive. In certain embodiments, L¹ represents alinker 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20consecutive covalently bonded atoms in length. In certain embodiments,L¹ represents a linker 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15consecutive covalently bonded atoms in length.

It should be generally understood that multiple instances of a givenvariable or group present in a linker may optionally differ. Thus, infurther defining the linker L¹, it is generally helpful to furtherdistinguish multiple instances of a given variable with differentnumbers.

For example, in certain embodiments, -L¹-R^(H) represents a group of theformula:

which may also be depicted as:

wherein n3 and n4 are as defined for variable n, and are eachindependently an integer between 1 to 10, inclusive, and wherein Q,R^(W3) and R^(H) are as defined herein. In certain embodiments, n3 is 2or 3 and n4 is 1, 2, or 3.

In certain embodiments, -L¹-R^(H) represents a group of the formula:

which may also be depicted as:

wherein n1, n2, n3, and n4 are as defined for variable n, and are eachindependently an integer between 1 to 10, inclusive, and wherein Q,R^(W3) and R^(H) are as defined herein. In certain embodiments, n1 is 1,n2 is 1 or 2, n3 is 1, and n4 is 1, 2, or 3.

In certain embodiments, -L¹-R^(H) represents a group of the formula:

which may also be depicted as:

wherein n3 and n4 are as defined for variable n, and are eachindependently an integer between 1 to 10, inclusive, and wherein G₁, G₂,Q, R^(W3), and R^(H) are as defined herein. In certain embodiments, n3is 2 or 3 and n4 is 1, 2, or 3.

In certain embodiments, -L¹-R^(H) represents a group of the formula:

which may also be depicted as:

wherein n1, n2, n3, and n4 are as defined for variable n, and are eachindependently an integer between 1 to 10, inclusive, and wherein G₁, G₂,Q, R^(W3) and R^(H) are as defined herein. In certain embodiments, n1 is1, n2 is 1 or 2, n3 is 1, and n4 is 1, 2, or 3.

In certain embodiments, -L¹-R^(H) represents a group of the formula:

wherein n is an integer between 1 to 10, inclusive, and wherein R^(W3)and R^(H) are as defined herein. In certain embodiments, n is 1, 2, or3.

In certain embodiments, -L¹-R^(H) represents a group of the formula:

wherein R^(H) is as defined herein.

In certain embodiments, -L¹-R^(H) represents a group of the formula:

wherein n is an integer between 1 to 10, inclusive, and wherein G₁, G₂,Q, R^(W3) and R^(H) are as defined herein. In certain embodiments, n is1, 2, or 3.

In certain embodiments, -L¹-R^(H) represents a group of the formula:

wherein G₁, G₂, and R^(H) are as defined herein.

In certain embodiments, -L¹-R^(H) represents a group of the formula:

wherein R^(H) is as defined herein.

In certain embodiments, -L¹-R^(H) represents a group of the formula:

wherein R^(H) is as defined herein.

Hydrophobic Group R^(H)

As described herein, R^(H) represents a hydrophobic group selected fromthe group consisting of substituted and unsubstituted aryl, substitutedand unsubstituted heteroaryl, substituted and unsubstituted carbocyclyl,substituted and unsubstituted heterocyclyl, substituted andunsubstituted aralkyl, substituted and unsubstituted heteroarylalkyl,substituted and unsubstituted carbocycylalkyl, and substituted andunsubstituted heterocyclylalkyl.

In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted aryl or substituted or unsubstituted aralkyl moiety. Incertain embodiments, R^(H) is a hydrophobic substituted or unsubstitutedaryl moiety, e.g., substituted or unsubstituted phenyl, substituted orunsubstituted biphenyl, substituted or unsubstituted naphthyl, orsubstituted or unsubstituted anthracenyl. In certain embodiments, R^(H)is a hydrophobic substituted or unsubstituted aralkyl moiety, e.g.,substituted or unsubstituted benzyl (—CH₂-phenyl), substituted orunsubstituted diphenylmethyl, substituted or unsubstituted trityl,substituted or unsubstituted biphenylmethyl, substituted orunsubstituted naphthylmethyl, or substituted or unsubstitutedanthracenylmethyl.

In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted aryl moiety, e.g., of the formula:

wherein each occurrence of R^(H1) and R^(H2) is independently halogen(e.g., fluoro, bromo, iodo, or chloro), alkyl (e.g., methyl, ethyl,propyl, isopropyl, tertbutyl), haloalkyl (e.g., difluoromethyl,perfluoromethyl), alkoxy (e.g., methoxy, ethoxy, isopropoxy), ordialkylamino (e.g., dimethylamino, diethylamino); and p and q areindependently 0, 1, 2, or 3. In certain embodiments, each occurrence ofR^(H1) and R^(H2) is independently fluoro, bromo, iodo, chloro, methyl,ethyl, propyl, isopropyl, tertbutyl, difluoromethyl, perfluoromethyl,methoxy, ethoxy, isopropoxy, dimethylamino, or diethylamino. In certainembodiments, p is 0 or 1. In certain embodiments, q is 0 or 1. Incertain embodiments, p is 0. In certain embodiments, q is 0. In certainembodiments, p is 0, and q is 0.

In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted aralkyl moiety, e.g., of the formula:

wherein each occurrence of R^(H1), R^(H2), and R^(H3) is independentlyhalogen (e.g., fluoro, bromo, iodo, or chloro), alkyl (e.g., methyl,ethyl, propyl, isopropyl, tertbutyl), haloalkyl (e.g., difluoromethyl,perfluoromethyl), alkoxy (e.g., methoxy, ethoxy, isopropoxy), ordialkylamino (e.g., dimethylamino, diethylamino); and p, q, and r areindependently 0, 1, 2, or 3. In certain embodiments, each occurrence ofR^(H1), R^(H2), and R^(H3) is independently fluoro, bromo, iodo, chloro,methyl, ethyl, propyl, isopropyl, tertbutyl, difluoromethyl,perfluoromethyl, methoxy, ethoxy, isopropoxy, dimethylamino, ordiethylamino. In certain embodiments, p is 0 or 1. In certainembodiments, q is 0 or 1. In certain embodiments, r is 0 or 1. Incertain embodiments, p is 0. In certain embodiments, q is 0. In certainembodiments, r is 0. In certain embodiments, p is 0, q is 0, and r is 0.

In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted heteroaryl or substituted or unsubstituted heteroarylalkylmoiety. In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted heteroaryl moiety, e.g., substituted or unsubstituted5-membered heteroaryl or substituted or unsubstituted 6-memberedheteroaryl. In certain embodiments, R^(H) is a hydrophobic substitutedor unsubstituted heteroarylaralkyl moiety, e.g., substituted orunsubstituted 5-membered heteroarylmethyl or substituted orunsubstituted 6-membered heteroarylmethyl.

In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted carbocyclyl or substituted or unsubstitutedcarbocycylalkyl moiety. In certain embodiments, R^(H) is a hydrophobicsubstituted or unsubstituted carbocyclyl moiety, e.g., aC₅₋₁₄carbocyclyl moiety which may be monocyclic, bicyclic, or tricyclicand/or fused, bridged, or spiro-fused, e.g., substituted orunsubstituted C₅₋₁₃carbocyclyl, substituted or unsubstitutedC₅₋₁₂carbocyclyl, substituted or unsubstituted C₅₋₁₁carbocyclyl,substituted or unsubstituted C₅₋₁₀carbocyclyl, substituted orunsubstituted C₅₋₉carbocyclyl, substituted or unsubstitutedC₅₋₈carbocyclyl, substituted or unsubstituted C₅₋₇carbocyclyl,substituted or unsubstituted C₃₋₆carbocyclyl, substituted orunsubstituted C₃₋₄carbocyclyl, substituted or unsubstituted C₄₋₅carbocyclyl, or substituted or unsubstituted C₅₋₆ carbocyclyl. Incertain embodiments, R^(H) is a hydrophobic substituted or unsubstitutedfused bicyclic carbocyclyl, e.g., substituted or unsubstituted cis- ortrans-decalin. In certain embodiments, R^(H) is a hydrophobicsubstituted or unsubstituted fused tricyclic carbocyclyl, e.g.,substituted or unsubstituted fluorenyl. In certain embodiments, R^(H) isa hydrophobic substituted or unsubstituted spiro-fused bicycliccarbocyclyl, e.g., substituted or unsubstituted spiropentane. In certainembodiments, R^(H) is a hydrophobic substituted or unsubstituted bridgedbicyclic carbocyclyl, e.g., substituted or unsubstituted norbornane,norbornene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene,bicyclo[3.2.1]octane, or bicyclo[2.2.1]heptan-2-one. In certainembodiments, R^(H) is a hydrophobic substituted or unsubstituted bridgedtricyclic carbocyclyl moiety, e.g., substituted or unsubstitutedadamantane. In certain embodiments, R^(H) is a hydrophobic substitutedor unsubstituted carbocycylalkyl moiety, e.g., hydrophobic substitutedor unsubstituted carbocycylmethyl.

In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted carbocyclyl moiety, e.g., of the formula:

wherein each occurrence of R^(H1) and R^(H2) is independently halogen(e.g., fluoro, bromo, iodo, or chloro), alkyl (e.g., methyl, ethyl,propyl, isopropyl, tertbutyl), haloalkyl (e.g., difluoromethyl,perfluoromethyl), alkoxy (e.g., methoxy, ethoxy, isopropoxy), ordialkylamino (e.g., dimethylamino, diethylamino); and p and q areindependently 0, 1, 2, or 3. In certain embodiments, each occurrence ofR^(H1) and R^(H2) is independently fluoro, bromo, iodo, chloro, methyl,ethyl, propyl, isopropyl, tertbutyl, difluoromethyl, perfluoromethyl,methoxy, ethoxy, isopropoxy, dimethylamino, or diethylamino. In certainembodiments, p is 0 or 1. In certain embodiments, q is 0 or 1. Incertain embodiments, p is 0. In certain embodiments, q is 0. In certainembodiments, p is 0, and q is 0.

In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted carbocyclylalkyl moiety, e.g., of the formula:

wherein each occurrence of R^(H1) and R^(H2) is independently halogen(e.g., fluoro, bromo, iodo, or chloro), alkyl (e.g., methyl, ethyl,propyl, isopropyl, tertbutyl), haloalkyl (e.g., difluoromethyl,perfluoromethyl), alkoxy (e.g., methoxy, ethoxy, isopropoxy), ordialkylamino (e.g., dimethylamino, diethylamino); and p and q areindependently 0, 1, 2, or 3. In certain embodiments, each occurrence ofR^(H1) and R^(H2) is independently fluoro, bromo, iodo, chloro, methyl,ethyl, propyl, isopropyl, tertbutyl, difluoromethyl, perfluoromethyl,methoxy, ethoxy, isopropoxy, dimethylamino, or diethylamino. In certainembodiments, p is 0 or 1. In certain embodiments, q is 0 or 1. Incertain embodiments, p is 0. In certain embodiments, q is 0. In certainembodiments, p is 0, and q is 0.

In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted heterocyclyl or substituted or unsubstitutedheterocyclylalkyl moiety. In certain embodiments, R^(H) is a hydrophobicsubstituted or unsubstituted heterocyclyl moiety, e.g., a 5-14-memberedheterocyclyl which may be monocyclic, bicyclic, or tricyclic and/or afused, bridged, or spiro-fused moiety, e.g., substituted orunsubstituted 5-13-membered heterocyclyl, substituted or unsubstituted5-12-membered heterocyclyl, substituted or unsubstituted 5-11-memberedheterocyclyl, substituted or unsubstituted 5-10-membered heterocyclyl,substituted or unsubstituted 5-9-membered heterocyclyl, substituted orunsubstituted 5-8-membered heterocyclyl, substituted or unsubstituted5-7-membered heterocyclyl, substituted or unsubstituted 3-6-memberedheterocyclyl, substituted or unsubstituted 3-4-membered heterocyclyl,substituted or unsubstituted 4-5-membered heterocyclyl, or substitutedor unsubstituted 5-6-membered heterocyclyl. In certain embodiments,R^(H) is a hydrophobic substituted or unsubstituted fused bicyclicheterocyclyl moiety. In certain embodiments, R^(H) is a hydrophobicsubstituted or unsubstituted fused tricyclic heterocyclyl moiety. Incertain embodiments, R^(H) is a hydrophobic substituted or unsubstitutedspiro-fused bicyclic heterocyclyl moiety. In certain embodiments, R^(H)is a hydrophobic substituted or unsubstituted bridged bicyclicheterocyclyl moiety. In certain embodiments, R^(H) is a hydrophobicsubstituted or unsubstituted bridged tricyclic heterocyclyl moiety. Incertain embodiments, R^(H) is a hydrophobic substituted or unsubstitutedheterocyclyl alkyl moiety, e.g., hydrophobic substituted orunsubstituted heterocyclylmethyl. Exemplary heterocylyl groups include,but are not limited to, piperidinyl, tetrahydropyranyl,dihydropyridinyl, and thianyl, piperazinyl, morpholinyl, dithianyl,dioxanyl, and triazinanyl moieties, which may comprise one or moreheterocycyl, carbocyclyl, aryl or heteroaryl rings fused thereto.

In certain embodiments, R^(H) is a hydrophobic substituted orunsubstituted heterocyclyl moiety, e.g., of the formula:

wherein each occurrence of R^(H1) and R^(H2) is independently halogen(e.g., fluoro, bromo, iodo, or chloro), alkyl (e.g., methyl, ethyl,propyl, isopropyl, tertbutyl), haloalkyl (e.g., difluoromethyl,perfluoromethyl), alkoxy (e.g., methoxy, ethoxy, isopropoxy), ordialkylamino (e.g., dimethylamino, diethylamino); and p and q areindependently 0, 1, 2, or 3. In certain embodiments, each occurrence ofR^(H1) and R^(H2) is independently fluoro, bromo, iodo, chloro, methyl,ethyl, propyl, isopropyl, tertbutyl, difluoromethyl, perfluoromethyl,methoxy, ethoxy, isopropoxy, dimethylamino, or diethylamino. In certainembodiments, p is 0 or 1. In certain embodiments, q is 0 or 1. Incertain embodiments, p is 0. In certain embodiments, q is 0. In certainembodiments, p is 0, and q is 0.

In certain embodiments, R^(H) is a hydrophobic group of the formula:

In certain embodiments, R^(H) is a hydrophobic group of the formula:

Optional Warhead -L²-R^(D)

As generally understood herein, M of Formula (I) represents a smallorganic molecule which covalently or non-covalently binds a kinase,e.g., a protein kinase.

In certain embodiments, the small organic molecule M includes and issubstituted with a group -L²-R^(D), wherein L² is a bond or a linker,and R^(D) is a group that covalently or non-covalently binds to thekinase.

In certain embodiments, L² is a bond or a linker selected from the groupconsisting of substituted and unsubstituted alkylene; substituted andunsubstituted alkenylene; substituted and unsubstituted alkynylene;substituted and unsubstituted heteroalkylene; substituted andunsubstituted heteroalkenylene; substituted and unsubstitutedheteroalkynylene; substituted and unsubstituted heterocyclylene;substituted and unsubstituted carbocyclylene; substituted andunsubstituted arylene; substituted and unsubstituted heteroarylene; andcombinations thereof.

In certain embodiments, L² is a bond.

In certain embodiments, L² is a linker comprising at least one instanceof substituted or unsubstituted alkylene, e.g., substituted orunsubstituted C₁₋₆alkylene, substituted or unsubstituted C₂₋₆alkylene,substituted or unsubstituted C₃₋₆alkylene, substituted or unsubstitutedC₄₋₆alkylene, substituted or unsubstituted C₅₋₆alkylene, substituted orunsubstituted C₂₋5alkylene, substituted or unsubstituted C₂₋₄alkylene,substituted or unsubstituted C₂₋₃alkylene, substituted or unsubstitutedC₁alkylene, substituted or unsubstituted C₂alkylene, substituted orunsubstituted C₃alkylene, substituted or unsubstituted C₄alkylene,substituted or unsubstituted C₅alkylene, or substituted or unsubstitutedC₆alkylene. In certain embodiments, L² is substituted or unsubstitutedalkylene.

In certain embodiments, L² is linker comprising at least one instance ofsubstituted or unsubstituted alkenylene, e.g., substituted orunsubstituted C₂₋₆alkenylene, substituted or unsubstitutedC₃₋₆alkenylene, substituted or unsubstituted C₄₋₆alkenylene, substitutedor unsubstituted C₅₋₆alkenylene, substituted or unsubstitutedC₂₋₅alkenylene, substituted or unsubstituted C₂₋₄alkenylene, substitutedor unsubstituted C₂₋₃alkenylene, substituted or unsubstitutedC₂alkenylene, substituted or unsubstituted C₃alkenylene, substituted orunsubstituted C₄alkenylene, substituted or unsubstituted C₅alkenylene,or substituted or unsubstituted C₆alkenylene. In certain embodiments, L²is substituted or unsubstituted alkenylene.

In certain embodiments, L² is linker comprising at least one instance ofsubstituted or unsubstituted alkynylene, e.g., substituted orunsubstituted C₂₋₆alkynylene, substituted or unsubstitutedC₃₋₆alkynylene, substituted or unsubstituted C₄₋₆alkynylene, substitutedor unsubstituted C₅₋₆alkynylene, substituted or unsubstitutedC₂₋₅alkynylene, substituted or unsubstituted C₂₋₄alkynylene, substitutedor unsubstituted C₂₋₃alkynylene, substituted or unsubstitutedC₂alkynylene, substituted or unsubstituted C₃alkynylene, substituted orunsubstituted C₄alkynylene, substituted or unsubstituted C₅alkynylene,or substituted or unsubstituted C₆alkynylene. In certain embodiments, L²is substituted or unsubstituted alkynylene.

In certain embodiments, L² is a linker comprising at least one instanceof substituted or unsubstituted heteroalkylene, e.g., substituted orunsubstituted heteroC₁₋₆alkylene, substituted or unsubstitutedheteroC₂₋₆alkylene, substituted or unsubstituted heteroC₃₋₆alkylene,substituted or unsubstituted heteroC₄₋₆alkylene, substituted orunsubstituted heteroC₅₋₆alkylene, substituted or unsubstitutedheteroC₂₋₅alkylene, substituted or unsubstituted heteroC₂₋₄alkylene,substituted or unsubstituted heteroC₂₋₃alkylene, substituted orunsubstituted heteroC₁alkylene, substituted or unsubstitutedheteroC₂alkylene, substituted or unsubstituted heteroC₃alkylene,substituted or unsubstituted heteroC₄alkylene, substituted orunsubstituted heteroC₅alkylene, or substituted or unsubstitutedheteroC₆alkylene. In certain embodiments, L² is substituted orunsubstituted heteroalkylene.

In certain embodiments, L² is a linker comprising at least one instanceof substituted or unsubstituted heteroalkenylene, e.g., substituted orunsubstituted heteroC₂₋₆alkenylene, substituted or unsubstitutedheteroC₃₋₆alkenylene, substituted or unsubstituted heteroC₄₋₆alkenylene, substituted or unsubstituted heteroC₅₋₆alkenylene,substituted or unsubstituted heteroC₂₋₅alkenylene, substituted orunsubstituted heteroC₂₋₄alkenylene, substituted or unsubstitutedheteroC₂₋₃alkenylene, substituted or unsubstituted heteroC₂alkenylene,substituted or unsubstituted heteroC₃alkenylene, substituted orunsubstituted heteroC₄alkenylene, substituted or unsubstitutedheteroC₅alkenylene, or substituted or unsubstituted heteroC₆alkenylene.In certain embodiments, L² is substituted or unsubstitutedheteroalkenylene.

In certain embodiments, L² is a linker comprising at least one instanceof substituted or unsubstituted heteroalkynylene, e.g., substituted orunsubstituted heteroC₂₋₆alkynylene, substituted or unsubstitutedheteroC₃₋₆alkynylene, substituted or unsubstituted heteroC₄₋₆alkynylene,substituted or unsubstituted heteroC₅₋₆alkynylene, substituted orunsubstituted heteroC₂₋₅alkynylene, substituted or unsubstitutedheteroC₂₋₄alkynylene, substituted or unsubstituted heteroC₂₋₃alkynylene,substituted or unsubstituted heteroC₂alkynylene, substituted orunsubstituted heteroC₃alkynylene, substituted or unsubstitutedheteroC₄alkynylene, substituted or unsubstituted heteroC₅alkynylene, orsubstituted or unsubstituted heteroC₆alkynylene. In certain embodiments,L² is substituted or unsubstituted heteroalkynylene.

In certain embodiments, L² is a linker comprising at least one instanceof substituted or unsubstituted heterocyclylene, e.g., substituted orunsubstituted 5- to 8-membered heterocyclylene, substituted orunsubstituted 5- to 7-membered heterocyclylene, substituted orunsubstituted 5- to 6-membered heterocyclylene, substituted orunsubstituted 5-membered heterocyclylene, substituted or unsubstituted6-membered heterocyclylene, substituted or unsubstituted 7-memberedheterocyclylene, or substituted or unsubstituted 8-memberedheterocyclylene. In certain embodiments, L² is substituted orunsubstituted heterocyclylene.

In certain embodiments, L² is a linker comprising at least one instanceof substituted or unsubstituted carbocyclylene, e.g., substituted orunsubstituted C₃₋₆ carbocyclylene, substituted or unsubstituted C₃₋₅carbocyclylene, substituted or unsubstituted C₃₋₄ carbocyclylene,substituted or unsubstituted C₃ carbocyclylene, substituted orunsubstituted C₄ carbocyclylene, substituted or unsubstituted C₅carbocyclylene, or substituted or unsubstituted C₆ carbocyclylene. Incertain embodiments, L² is substituted or unsubstituted carbocyclylene.

In certain embodiments, L² is a linker comprising at least one instanceof substituted or unsubstituted arylene, e.g., substituted orunsubstituted C₆ arylene (phenylene) or substituted or unsubstituted C₁₀arylene (naphthylene). In certain embodiments, L² is substituted orunsubstituted arylene.

In certain embodiments, L² is a linker comprising at least one instanceof substituted or unsubstituted heteroarylene, e.g., substituted orunsubstituted 5-membered heteroarylene or substituted or unsubstituted6-membered heteroarylene. In certain embodiments, L² is substituted orunsubstituted heteroarylene.

In certain embodiments, R^(D) is an electrophilic group that covalentlybinds a kinase, e.g., a protein kinase, by reaction with a nucleophilicmoiety, e.g., such as a cysteine in the ATP binding pocket of thekinase. In this instance, in certain embodiments, R^(D) is a group offormula:

wherein:

R^(D1) is hydrogen, halogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —CN, —NO₂, —OR^(D1a),—N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a), —CH₂N(R^(D1a))₂, —CH₂SR^(D1a),—C(═O)R^(D1a), —C(═O)OR^(D1a), —C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂,—C(═S)R^(D1a), —C(═S)OR^(D1a), —C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂,—C(═NR^(D1a))R^(D1a), —C(═NR^(D1a))OR^(D1a), C(═NR^(D1a))SR^(D1a), or—C(═NR^(D1a))N(R^(D1a))₂, wherein each occurrence of R^(D1a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D1a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

R^(D2) is hydrogen, halogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —CN, —NO₂, —OR^(D2a),—N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a), —CH₂N(R^(D2a))₂, —CH₂SR^(D2a),—C(═O)R^(D2a), —C(═O)OR^(D2a), —C(═O)SR^(D2a), —C(═O)N(R^(D2a))₂,—C(═S)R^(D2a), —C(═S)OR^(D2a), —C(═S)SR^(D2a), —C(═S)N(R^(D2a))₂,—C(═NR^(D2a))R^(D2a), —C(═NR^(D2a))OR^(D2a), —C(═NR^(D2a))SR^(D2a), and—C(═NR^(D2a))N(R^(D2a))₂, wherein each occurrence of R^(D2a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, or two R^(D2a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

R^(D3) is hydrogen, halogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(D3a), —N(R^(D3a))₂,—SR^(D3a), —CH₂OR^(D3a), —CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a),—C(═O)OR^(D3a), —C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a),—C(═S)OR^(D3a), —C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3a),—C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), or—C(═NR^(D3a))N(R^(D3a))₂ wherein each occurrence of R^(D3a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D3a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2)are joined to form an substituted or unsubstituted carbocyclic orsubstituted or unsubstituted heterocyclic ring;

R^(D4) is a leaving group selected from the group consisting of —Br,—Cl, —I, and —OS(═O)_(w)R^(D4a), wherein w is 1 or 2, and R^(D4a) issubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

X¹ is a bond or NR^(D5), wherein R^(D5) is hydrogen, C₁₋₆ alkyl, or anitrogen protecting group;

each instance of Y is independently O, S, or NR^(D6), wherein R^(D6) ishydrogen, C₁₋₆ alkyl, or a nitrogen protecting group; and

z is 0, 1, 2, 3, 4, 5, or 6.

In certain embodiments, R^(D) is a group of Formula (i-1), (i-3), or(i-20):

wherein each instance of X¹ is bond or NR^(D5), Y is independently O, S,or NR^(D6), and R^(D1), R^(D2) and R^(D3) are as defined herein. Incertain embodiments, X¹ is a bond. In certain embodiments, X¹ isNR^(D5). In certain embodiments, Y is O. In certain embodiments, R^(D1)is hydrogen. In certain embodiments, R^(D1) is —CN. In certainembodiments, R^(D2) is hydrogen. In certain embodiments, R^(D3) ishydrogen. In certain embodiments, R^(D2) is —CH₂N(R^(D2a))₂, and R^(D3)is hydrogen. In certain embodiments, R^(D2) is —CH₂N(R^(D3a))₂, andR^(D3) is hydrogen. In certain embodiments, R^(D2) and R^(D3) arehydrogen. In certain embodiments, R^(D1), R^(D2) and R^(D3) arehydrogen.

In certain embodiments, R^(D) is a group of Formula (i-19), (i-17), or(i-18):

wherein Y is independently O, S, or NR^(D6); and R^(D1), R^(D2), andR^(D3) are as defined herein. In certain embodiments, Y is O. In certainembodiments, R^(D1) is hydrogen. In certain embodiments, R^(D2) ishydrogen. In certain embodiments, R^(D2) is —CN. In certain embodiments,R^(D3) is substituted or unsubstituted alkyl.

In certain embodiments, R^(D) is a group of Formula (i-7) or (i-8):

wherein Y is independently O, S, or NR^(D6); and R^(D1), R^(D2), andR^(D3) are as defined herein. In certain embodiments, Y is O. In certainembodiments, R^(D1) is hydrogen. In certain embodiments, R^(D2) ishydrogen. In certain embodiments, R^(D3) is hydrogen.

In certain embodiments, R^(D) is a group of Formula (i-13) or (i-14):

wherein each instance of X¹ is bond or NR^(D5); Y is independently O, S,or NR^(D6); and R^(D1) and R^(D2) are as defined herein. In certainembodiments, X¹ is a bond. In certain embodiments, X¹ is NR^(D5). Incertain embodiments, Y is O. In certain embodiments, R^(D1) is hydrogen.In certain embodiments, R^(D1) is halogen, e.g., —F or —Cl. In certainembodiments, R^(D2) is hydrogen. In certain embodiments, R^(D2) ishalogen, e.g., —F or —Cl.

In certain embodiments, R^(D) is a group of Formula (i-11) or (i-12):

wherein each instance of X¹ is bond or NR^(D5); Y is independently O, S,or NR^(D6); z is 0, 1, 2, 3, 4, 5, or 6; and R^(D1) is as definedherein. In certain embodiments, X¹ is a bond. In certain embodiments, X¹is NR^(D5). In certain embodiments, Y is O. In certain embodiments z is0 or 1. In certain embodiments, R^(D1) is substituted or unsubstitutedalkyl.

In certain embodiments, R^(D) is a group of Formula (i-10), (i-16), or(i-9):

wherein each instance of X¹ is bond or NR^(D5); Y is independently O, S,or NR^(D6); z is 0, 1, 2, 3, 4, 5, or 6; and R^(D4) is a leaving groupselected from the group consisting of —Br, —Cl, —I, and—OS(═O)_(w)R^(D4a), wherein w is 1 or 2. In certain embodiments, X¹ is abond. In certain embodiments, X¹ is NR^(D5). In certain embodiments, Yis O. In certain embodiments, z is 0. In certain embodiments, z is 1.

In certain embodiments, R^(D) is a group of Formula (i-4) or (i-5):

wherein each instance of X¹ is bond or NR^(D5); and R^(D1) is as definedherein. In certain embodiments, X¹ is a bond. In certain embodiments, X¹is NR^(D5). In certain embodiments, R^(D1) is hydrogen.

In certain embodiments, R^(D) is a group of Formula (i-6):

wherein each instance of X¹ is bond or NR^(D5); Y is independently O, S,or NR^(D6); and R^(D1) is as defined herein. In certain embodiments, X¹is a bond. In certain embodiments, X¹ is NR^(D5). In certainembodiments, Y is O. In certain embodiments, R^(D1) is hydrogen.

Her3 Protein Kinase

In certain embodiments, the small organic molecule, even in the absenceof the hydrophobic moiety -L¹-R^(H), covalently or non-covalently bindsHer3 protein kinase.

Her3 (ErbB3) is a transmembrane receptor tyrosine protein kinase whichis overexpressed and deregulated in many cancers such as breast,ovarian, and non-small cell lung cancers, and specifically Her2 drivenbreast cancer, 22% of gefitinib-resistant non-small cell lung cancer,and as much as 53% of ovarian cancer. See, e.g., Baselga et al., Nat.Rev. Cancer (2009) 9:463; Lee-Hoeflich et al., Cancer Res. (2008)68:5878; Hammerman et al., Clin. Cancer Res. (2009) 15:7502; Tanner etal., J. Clin. Oncol. (2006) 24:4317. It is a member of the HER familywhich also includes: EGFR (ErbB1/Her1), Her2 (ErbB2), and Her4 (ErbB4).Among them, HER3 is unique because it has extremely low protein kinaseactivity and is considered to be a so-called “pseudo-kinase.” See, e.g.,Shi et al., Proc. Natl. Acad. Sci. USA (2010) 107:7692. Despite the lackof protein kinase activity, Her3 is often an essentialheterodimerization partner with EGFR and Her2, resulting in recruitmentand activation of PI3K to the plasma membrane. Her3 has been extensivelyvalidated as a promising oncology kinase target using genetic approachesand currently several antibodies directed against the extracellularligand-binding domain of Her3 are under clinical evaluation. See, e.g.,Sergina et al., Nature (2007) 445:437. Due to the weak kinase activityof Her3, there are currently no small molecules reported that caninhibit Her3 function, and the kinase is considered to be an“undruggable target.” For example, many small molecules which covalentlyor non-covalently bind to the ATP site of Her3, due to the low kinaseactivity of Her3, neither inhibit Her3-dependent proliferation norinhibit Her3 signaling. To overcome this problem, the inventorsenvisioned linking such small molecules to a hydrophobic tag such thatthe bi-functional molecule may, upon selectively binding Her3, thenselectively induce Her3 protein degradation, e.g., by unfolding andsubsequent degradation by the proteasome.

To discover chemical starting points for developing Her3 inhibitors, theinventors screened a library of 1,500 kinase-directed compounds usingthe LanthaScreen™ Eu methodology for compounds that could bind to theATP-site of Her3. The most potent Her3 binder from this screen wasKIN001-111, which evolved to TX-1-85-1 using structure-based drug designand iterative rounds of synthesis and evaluation. See, e.g., Stachlewitzet al., J Pharmacol Exp Ther. (2005) 315:36-41. TX1-85-1 possesses anacrylamide which forms a covalent bond with Cys721 in the Her3 ATPbinding site (as shown by mass spectrometry). TX1-85-1 is a potentbinder of Her3, and it can covalently label Her3 in cells.

To evaluate the ability of covalent Her3 inhibitors to inhibitHer3-dependent growth, two established cells lines, PC9 GR4 and Ocvar8,were utilized that have been shown to be Her3-dependent using siRNAmediated depletion of Her3. At 5 μM of TX1-85-1, a concentrationsufficient to fully label Her3 in cells, there was no observed growthinhibition of PC9 GR4 or Ovcar8 cells and no observed inhibition of thephosphorylation of downstream effectors of Her3, such as Erk and Akt. Toovercome this problem, the inventors appended an adamantane hydrophobictag via a linker to TX1-85-1 to yield TX2-62-1, which maintained potentand covalent Her3 binding ability. However, TX2-62-1 still did notinhibit Her3-dependent growth. Without wishing to be bound by anyparticular theory, the inventors hypothesize that this lack ofinhibition is the result of poor cell penetration of TX2-62-1 due to itshigh molecular weight (MW=828.5). The inventors tested this hypothesisby designing a strategy whereby the two halves of TX2-62-1 (TX2-49-1 andTX2-57-1) were brought together inside of a cell via oxime formation.See Scheme 1 below. The inventors discovered that formation of TX2-62-1via intracellular oxime formation resulted in efficient degradation ofHer3, inhibition of Her3-dependent signaling, and loss of viability ofHer3-addicted cells. As expected, when TX2-62-1 was washed out, Her3protein was resynthesized and cell proliferation resumed.

Based in part on the work with TX1-85-1 and TX2-62-1, the inventorsenvisioned certain desirable, but non-limiting, characteristics in ahydrophobically tagged compound of Formula (I), and specifically in acompound of Formula (II):

(1) In certain embodiments, the linker L¹, joining the small molecule(M) to the hydrophobic tag R^(H), is long enough in order for thehydrophobic tag R^(H) to be exposed for ligase recognition but shortenough that the compound of Formula (I) or (II) will have a low enoughmolecular weight to be cell permeable, e.g., for example, in certainembodiments, the linker L¹ is 4 to 20 consecutive covalently bondedatoms in length, inclusive. In certain embodiments, the linker L¹ is 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive covalently bondedatoms in length.

(2) In certain embodiments, the compound of Formula (I) or (II) has alow enough molecular weight, e.g., between about 400 and about 800g/mol, between about 500 and about 800 g/mol, between about 600 andabout 800 g/mol, or between about 700 and about 800 g/mol, in order toensure sufficient cell penetration.

(3) In certain embodiments, the compound of Formula (I) or (II) has ahigh enough polarity, e.g., as measured by a c log P of less than 5, inorder to ensure cell penetration, e.g., between about −8 and about 4.9,between about −8 and about 4, between about −8 and about 3, betweenabout −8 and about 2, between about −8 and about 1, or between about −8and about 0, inclusive. The c log P value of a molecule, which is thelogarithm of its partition coefficient between n-octanol and waterlog(_(coctanol/cwater)), is a well-established measure of the molecule'shydrophilicity. Low hydrophilicities and therefore high log P valuescause poor absorption or permeation.

(4) In certain embodiments, the terminal hydrophobic tag R^(H) hasenough hydrophobic character in order to induce the desired proteindegradation of the target. Hydrophobic character of a particular groupmay be optimized by first limiting the number of hydrogen bond donors,e.g., to zero donors, and optionally by also limiting the number ofhydrogen bond acceptors, e.g., optionally to zero acceptors.

(5) Of course, in its entirety, the compound of Formula (I) or (II) maycomprise a number of hydrogen bond donors and acceptors, but in certainembodiments, the overall number of hydrogen bond donors and acceptorspresent is also limited, for example, to 5 or less hydrogen bond donors,and/or to 10 or less hydrogen bond acceptors. In certain embodiments,the compound of Formula (I) or (II) has 0, 1, 2, 3, 4, or 5 hydrogenbond donors; e.g., for example, 0, 1, 2, 3, 4, or 5 —OH, —SH, or —NHgroups. In certain embodiments, the compound of Formula (I) or (II) has0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hydrogen bond acceptors, e.g., forexample, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 O, S, or N atoms which donot comprise a hydrogen attached thereto.

(6) Furthermore, in certain embodiments, the compound of Formula (I) or(II) comprises an additional functionality which covalently ornon-covalently binds the kinase, e.g., a protein kinase such as a Her3protein kinase. This additional functionality, also referred to as a“warhead,” is not attached to the linker or hydrophobic tag, but isappended to another area on the molecule such that the warhead does notinterfere with the linker-tag's interaction with the protein kinase. Incertain embodiments, the warhead non-covalently binds to the ATP bindingsite of kinase, e.g., the Her3 protein kinase. In certain embodiments,the warhead covalently binds to the ATP binding site of the kinase,e.g., the Her3 protein kinase. In certain embodiments, the warheadcovalently binds to a cysteine residue in the ATP binding site ofkinase, e.g., the Her3 protein kinase, e.g., Cys721 of the Her3 proteinkinase.

Compounds of the present invention may comprise one or more of the abovecharacteristics.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof;wherein:

L¹, L², R^(H), and R^(D) are as defined herein;

Ring A is substituted or unsubstituted carbocyclylene, substituted orunsubstituted heterocyclylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

each occurrence of R^(B) is independently selected from the groupconsisting of hydrogen, acyl, substituted and unsubstituted alkyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkynyl, substituted and unsubstituted carbocyclyl, substituted andunsubstituted heterocyclyl, substituted and unsubstituted aryl,substituted and unsubstituted heteroaryl, a nitrogen protecting group,or two R^(B) groups are joined to form an substituted or unsubstitutedheterocyclic or substituted or unsubstituted heteroaryl ring;

each instance of R^(C) is independently hydrogen, halogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(C1),—N(R^(C1))₂, —SR^(C1), —C(═O)R^(C1), —C(═O)OR^(C1), —C(═O)SR^(C1),—C(═O)N(R^(C1))₂, —NR^(C1)(═O)R^(C1), —NR^(C1)C(═O)OR^(C1),—NR^(C1)C(═O)SR^(C1), or —NR^(C1)C(═O)N(R^(C1))₂, wherein eachoccurrence of R^(C1) is independently hydrogen, acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, and a sulfur protecting group when attachedto a sulfur atom, or two R^(C1) groups are joined to form an substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring;

a is 0, 1, 2, 3, or 4; and

b is 0 or 1.

As generally defined above, each occurrence of R^(B) is independentlyhydrogen, acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group, or two R^(B) groups are joinedto form an substituted or unsubstituted heterocyclic or substituted orunsubstituted heteroaryl ring.

In certain embodiments, each instance of R^(B) is hydrogen. In certainembodiments, at least one instance of R^(B) is hydrogen, and at leastone instance of R^(B) is a non-hydrogen group, i.e., acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, or anitrogen protecting group. In certain embodiments, two R^(B) groups arejoined to form an substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring.

As generally defined above, each instance of R^(C) is independentlyhydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(C1), —N(R^(C1))₂, —SR^(C1), —C(═O)R^(C1),—C(═O)OR^(C1), —C(═O)SR^(C1), —C(═O)N(R^(C1))₂, —NR^(C1)C(═O)R^(C1),—NR^(C1)C(═O)OR^(C1), —NR^(C1)C(═O)SR^(C1), or —NR^(C1)C(═O)N(R^(C1))₂;and a is 0, 1, 2, 3, or 4.

In certain embodiments, a is 0, and R^(C) is absent. In certainembodiments, a is 1, 2, 3, or 4.

In certain embodiments, wherein a is 1, 2, 3, or 4, at least oneinstance of R^(C) is —OR^(C1), —N(R^(C1))₂, —SR^(C1), —C(═O)R^(C1),—C(═O)OR^(C1), —C(═O)SR^(C1), —C(═O)N(R^(C1))₂, —NR^(C1)C(═O)R^(C1),—NR^(C1)C(═O)OR^(C1), —NR^(C1)C(═O)SR^(C1), or —NR^(C1)C(═O)N(R^(C1))₂.In certain embodiments, at least one instance of R^(C) is —OR^(C1). Incertain embodiments, at least one instance of R^(C) is —N(R^(C1))₂. Incertain embodiments, at least one instance of R^(C) is —SR^(C1). Incertain embodiments, at least one instance of R^(C) is —C(═O)R^(C1). Incertain embodiments, at least one instance of R^(C) is —C(═O)OR^(C1). Incertain embodiments, at least one instance of R^(C) is —C(═O)SR^(C1). Incertain embodiments, at least one instance of R^(C) is —C(═O)N(R^(C1))₂.In certain embodiments, at least one instance of R^(C) is—NR^(C1)C(═O)R^(C1). In certain embodiments, at least one instance ofR^(C) is —NR^(C1)C(═O)OR^(C1). In certain embodiments, at least oneinstance of R^(C) is —NR^(C1)C(═O)SR^(C1). In certain embodiments, atleast one instance of R^(C) is —NR^(C1)C(═O)N(R^(C1))₂.

In certain embodiments, a is 1. In certain embodiments, a is 2.

In certain embodiments, a is 1, and b is 1. In this instance, in certainembodiments, the groups R^(C) and -L²-R^(D) are ortho to each other. Incertain embodiments, the groups R^(C) and -L²-R^(D) are meta to eachother. In certain embodiments, the groups R^(C) and -L²-R^(D) are parato each other.

In certain embodiments, a is 2, and b is 0. In this instance, in certainembodiments, the two groups R^(C) are ortho to each other. In certainembodiments, the two groups R^(C) are meta to each other. In certainembodiments, the two groups R^(C) are para to each other.

In certain embodiments, the compound of Formula (II) reduces proteinkinase activity by targeted degradation of Her3. In certain embodiments,the compound of Formula (II) reduces protein kinase activity by inducingunfolding of the protein. In certain embodiments, the compound ofFormula (II) reduces protein kinase activity by covalently binding toHer3. In certain embodiments, the compound of Formula (II) reducesprotein kinase activity by non-covalently binding to Her3. In certainembodiments, wherein b is 1, and group -L²-R^(D) is present, thecompound of Formula (II) covalently binds to Her3 protein kinase. Incertain embodiments, wherein b is 0, and group -L²-R^(D) is absent, thecompound of Formula (II) non-covalently binds to Her3 protein kinase. Incertain embodiments, the reduction of protein kinase activity results inthe inhibition of Her3-dependent signaling and/or loss of viability ofHer3-addicted cells.

For example, in certain embodiments of Formula (II), wherein a is 1, andb is 1 (and thus the group -L²-R^(D) is present), provided is a compoundof Formula (II-a):

or a pharmaceutically acceptable salt thereof; wherein R^(C) is asdefined herein. In certain embodiments, R^(C) is hydrogen, —OR^(C1),—N(R^(C1))₂, or —SR^(C1). In certain embodiments, R^(C) is —OR^(C1),wherein R^(C1) is substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In certain embodiments, R^(C) is —OR^(C1), wherein R^(C1) issubstituted or unsubstituted aryl, e.g., substituted or unsubstitutedphenyl.

In certain embodiments of Formula (II-a), provided is a compound ofFormula (II-a1):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(C1) is substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In certain embodiments of Formula (II), wherein a is 2, and b is 0 (andthus the group -L²-R^(D) is absent), provided is a compound of Formula(II-b):

or a pharmaceutically acceptable salt thereof; wherein each instance ofR^(C) is as defined herein. In certain embodiments, one instance ofR^(C) is hydrogen, —OR^(C1), —N(R^(C1))₂, or —SR^(C1). In certainembodiments, one instance of R^(C) is —OR^(C1), wherein R^(C1) issubstituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Incertain embodiments, R^(C) is —OR^(C1), wherein R^(C1) is substituted orunsubstituted alkyl, e.g., methyl. In certain embodiments, one R^(C) is—C(═O)R^(C1), —C(═O)OR^(C1), —C(═O)SR^(C1), —C(═O)N(R^(C1))₂,—NR^(C1)C(═O)R^(C1), —NR^(C1)C(═O)OR^(C1), —NR^(C1)C(═O)SR^(C1), or—NR^(C1)C(═O)N(R^(C1))₂. In certain embodiments, one R^(C) is—C(═O)R^(C1), —C(═O)OR^(C1), —C(═O)SR^(C1), —C(═O)N(R^(C1))₂,—NHC(═O)R^(C1), —NHC(═O)OR^(C1), —NHC(═O)SR^(C1), or —NHC(═O)N(R^(C1))₂.In certain embodiments, one R^(C) is —C(═O)R^(C1), —C(═O)OR^(C1),—C(═O)SR^(C1), —C(═O)N(R^(C1))₂, —NHC(═O)R^(C1), —NHC(═O)OR^(C1),—NHC(═O)SR^(C1), or —NHC(═O)N(R^(C1))₂, wherein one R^(C1) issubstituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Incertain embodiments, one R^(C) is —C(═O)R^(C1), —C(═O)OR^(C1),—C(═O)SR^(C1), —C(═O)N(R^(C1))₂, —NHC(═O)R^(C1), —NHC(═O)OR^(C1),—NHC(═O)SR, or —NHC(═O)N(R^(C1))₂, wherein one R^(C1) is substituted orunsubstituted heteroaryl, e.g., a substituted or unsubstituted bicyclicheteroaryl moiety, such as indolyl.

In certain embodiments of Formula (II-b), provided is a compound ofFormula (II-b1):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(C1) is substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In certain embodiments, R^(C) is —C(═O)R^(C1),—C(═O)OR^(C1), —C(═O)SR^(C1), —C(═O)N(R^(C1))₂, —NHC(═O)R^(C1),—NHC(═O)OR^(C1), —NHC(═O)SR^(C1), or —NHC(═O)N(R^(C1))₂.

In certain embodiments of Formula (II-b), provided is a compound ofFormula (II-b2):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(C) is —OR^(C1), wherein R^(C1) is substituted or unsubstituted alkyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In certain embodiments, R^(C1) of the amidemoiety is a substituted or unsubstituted heteroaryl moiety, e.g., asubstituted or unsubstituted bicyclic heteroaryl moiety, such asindolyl.

In certain embodiments of Formula (II-b), provided is a compound ofFormula (II-b3):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(C1) of the —OR^(C1) group is substituted or unsubstituted alkyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In certain embodiments, R^(C1) of the amidemoiety is a substituted or unsubstituted heteroaryl moiety, e.g., asubstituted or unsubstituted bicyclic heteroaryl moiety, such asindolyl.

As generally defined above, Ring A is substituted or unsubstitutedcarbocyclylene, substituted or unsubstituted heterocyclylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. It is understood that Ring A is already substituted withthe group -L¹-R^(H). Thus, “substituted” in the context of Ring A refersto additional substitution(s) on the ring. In certain embodiments, RingA is not further substituted (unsubstituted Ring A). In certainembodiments, Ring A is additionally substituted (substituted Ring A).

In certain embodiments, Ring A is substituted or unsubstituted arylene,e.g., substituted or unsubstituted phenylene or substituted orunsubstituted naphthylene.

In certain embodiments, wherein Ring A is substituted or unsubstitutedphenylene, the compound of Formula (II) is of Formula (II-c):

or a pharmaceutically acceptable salt thereof,wherein:

each occurrence of R^(A) is, independently, hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1), or—C(═O)OR^(A1) wherein each occurrence of R^(A1) is independentlyhydrogen, acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(A1)groups are joined to form an substituted or unsubstituted heterocyclicor substituted or unsubstituted heteroaryl ring; and

c is 0 or 1.

In certain embodiments of Formula (II-c), c is 0, and R^(A) is absent.In certain embodiments, c is 1, and R^(A) is present, either ortho,meta, or para to the point of attachment of the phenylene group to thepyrazolyl ring. In certain embodiments, the group L¹-R^(H) is presenteither ortho, meta, or para to the point of attachment of the phenylenegroup to the pyrazolyl ring. In certain embodiments, b is 0. In certainembodiments, b is 1, L² is a bond, and R^(D) is a group of Formula(i-1). In certain embodiments, each instance of R^(B) is hydrogen. Incertain embodiments, L¹ is 5 to 15 consecutive covalently bonded atomsin length. In certain embodiments, R^(H) is a group of formula:

For example, in certain embodiments of Formula (II-c), wherein the groupL¹-R^(H) is para to the point of attachment of the phenylene group tothe pyrazolyl ring, provided is a compound of Formula (II-c1):

or a pharmaceutically acceptable salt thereof. In certain embodiments ofFormula (II-c1), c is 0, and R^(A) is absent. In certain embodiments, cis 1, and R^(A) is present, either ortho, meta, or para to the point ofattachment of the phenylene group to the pyrazolyl ring. In certainembodiments, the group L¹-R^(H) is present either ortho, meta, or parato the point of attachment of the phenylene group to the pyrazolyl ring.In certain embodiments, b is 0. In certain embodiments, b is 1, L² is abond, and R^(D) is a group of Formula (i-1). In certain embodiments,each instance of R^(B) is hydrogen. In certain embodiments, L¹ is 5 to15 consecutive covalently bonded atoms in length. In certainembodiments, R^(H) is a group of formula:

In certain embodiments, Ring A is substituted or unsubstitutedheteroarylene, e.g., a substituted or unsubstituted 5- to 6-memberedheteroarylene. In certain embodiments, Ring A is a 6-memberedheteroarylene, e.g., pyridinylene.

For example, in certain embodiments, wherein Ring A is substituted orunsubstituted pyridinylene, provided is a compound of Formula (II-d):

or a pharmaceutically acceptable salt thereof, wherein:

each occurrence of R^(A) is, independently, hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1), or—C(═O)OR^(A1), wherein each occurrence of R^(A1) is independentlyhydrogen, acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(A1)groups are joined to form an substituted or unsubstituted heterocyclicor substituted or unsubstituted heteroaryl ring; and

c is 0 or 1.

In certain embodiments of Formula (II-d), c is 0, and R^(A) is absent.In certain embodiments, c is 1, and R^(A) is present, either ortho,meta, or para to the point of attachment of the pyridinylene group tothe pyrazolyl ring. In certain embodiments, the group L¹-R^(H) ispresent either ortho, meta, or para to the point of attachment of thepyridinylene group to the pyrazolyl ring. In certain embodiments, b is0. In certain embodiments, b is 1, L² is a bond, and R^(D) is a group ofFormula (i-1). In certain embodiments, each instance of R^(B) ishydrogen. In certain embodiments, L¹ is 5 to 15 consecutive covalentlybonded atoms in length. In certain embodiments, R^(H) is a group offormula:

In certain embodiments, Ring A is substituted or unsubstitutedcarbocyclylene, e.g., a substituted or unsubstituted C₃₋₈carbocyclylene. In certain embodiments, Ring A is a substituted orunsubstituted cyclopropylene, substituted or unsubstitutedcyclobutylene, substituted or unsubstituted cyclopentylene, substitutedor unsubstituted cyclohexylene, substituted or unsubstitutedcycloheptylene, or substituted or unsubstituted cyclooctylene.

For example, in certain embodiments, wherein Ring A is substituted orunsubstituted C₃₋₈ carbocyclylene, provided is a compound of Formula(II-e):

or a pharmaceutically acceptable salt thereof,wherein:

each occurrence of R^(A) is, independently, hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1), or—C(═O)OR^(A1), wherein each occurrence of R^(A1) is independentlyhydrogen, acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(A1)groups are joined to form an substituted or unsubstituted heterocyclicor substituted or unsubstituted heteroaryl ring;

c is 0 or 1; and

d is 0, 1, 2, 3, 4, or 5.

In certain embodiments of Formula (II-e), c is 0 and R^(A) is absent. Incertain embodiments, c is 1. In certain embodiments, b is 0. In certainembodiments, b is 1, L² is a bond, and R^(D) is a group of Formula(i-1). In certain embodiments, each instance of R^(B) is hydrogen. Incertain embodiments, L¹ is 5 to 15 consecutive covalently bonded atomsin length. In certain embodiments, R^(H) is a group of formula:

For example, in certain embodiments, wherein Ring A is substituted orunsubstituted C₃₋₈ carbocyclylene, provided is a compound of Formula(II-e1), (II-e2), (II-e3), (II-e4), (II-e5), or (II-e6):

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formula (II-e1), (II-e2), (II-e3), (II-e4),(II-e5), or (II-e6), c is 0, and R^(A) is absent. In certainembodiments, c is 1. In certain embodiments, b is 0. In certainembodiments, b is 1, L² is a bond, and R_(D) is a group of Formula(i-1). In certain embodiments, each instance of R^(B) is hydrogen. Incertain embodiments, L¹ is 5 to 15 consecutive covalently bonded atomsin length. In certain embodiments, R^(H) is a group of formula:

For example, in certain embodiments of Formula (II-e3) provided is acompound of Formula (II-e3a):

or a pharmaceutically acceptable salt thereof. In certain embodiments ofFormula (II-e3) or (II-e3a), c is 0, and R^(A) is absent. In certainembodiments, c is 1, and R^(A) is present either at the 2 or 3 positionfrom the point of attachment of the cyclopentylene group to thepyrazolyl ring. In certain embodiments, the group L¹-R^(H) is presenteither at the 2 or 3 position from the point of attachment of thecyclopentylene group to the pyrazolyl ring. In certain embodiments, b is0. In certain embodiments, b is 1, L² is a bond, and R^(D) is a group ofFormula (i-1). In certain embodiments, each instance of R^(B) ishydrogen. In certain embodiments, L¹ is 5 to 15 consecutive covalentlybonded atoms in length. In certain embodiments, R^(H) is a group offormula:

For example, in certain embodiments of Formula (II-e4) provided is acompound of Formula (II-e4a):

or a pharmaceutically acceptable salt thereof. In certain embodiments ofFormula (II-e4) or (II-e4a), c is 0, and R^(A) is absent. In certainembodiments, c is 1, and R^(A) is present, either at the 2, 3, or 4position from the point of attachment of the cyclohexylene group to thepyrazolyl ring. In certain embodiments, the group L¹-R^(H) is presenteither at the 2, 3, or 4 position from the point of attachment of thecyclohexylene group to the pyrazolyl ring. In certain embodiments, b is0. In certain embodiments, b is 1, L² is a bond, and R^(D) is a group ofFormula (i-1). In certain embodiments, each instance of R^(B) ishydrogen. In certain embodiments, L¹ is 5 to 15 consecutive covalentlybonded atoms in length. In certain embodiments, R^(H) is a group offormula:

In certain embodiments, Ring A is substituted or unsubstitutedheterocyclylene, e.g., substituted or unsubstituted 3- to 8-memberedheterocyclylene, e.g., substituted or unsubstituted 3-memberedheterocyclylene, substituted or unsubstituted 4-memberedheterocyclylene, substituted or unsubstituted 5-memberedheterocyclylene, substituted or unsubstituted 6-memberedheterocyclylene, substituted or unsubstituted 7-memberedheterocyclylene, or substituted or unsubstituted 8-memberedheterocyclylene. In certain embodiments, Ring A is substituted orunsubstituted 5-membered heterocyclylene, e.g., substituted orunsubstituted pyrrolidinylene. In certain embodiments, Ring A issubstituted or unsubstituted 6-membered heterocyclylene, e.g.,substituted or unsubstituted morpholinylene, substituted orunsubstituted piperidinylene, or substituted or unsubstitutedpiperazinylene.

For example, in certain embodiments, wherein Ring A is substituted orunsubstituted pyrrolidinylene, provided is a compound of Formula (II-f):

or a pharmaceutically acceptable salt thereof,wherein:

each occurrence of R^(A) is, independently, hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1) or—C(═O)OR^(A1), wherein each occurrence of R^(A1) is independentlyhydrogen, acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(A1)groups are joined to form an substituted or unsubstituted heterocyclicor substituted or unsubstituted heteroaryl ring; and

c is 0 or 1.

In certain embodiments of Formula (II-f), c is 0 and R^(A) is absent. Incertain embodiments, c is 1, and R^(A) is present, either at the 2 or 3position from the point of attachment of the pyrrolidinyl group to thepyrazolyl ring. In certain embodiments, the group L¹-R^(H) is presenteither at the 2 or 3 position from the point of attachment of thepyrrolidinyl group to the pyrazolyl ring. In certain embodiments, b is0. In certain embodiments, b is 1, L² is a bond, and R^(D) is a group ofFormula (i-1). In certain embodiments, each instance of R^(B) ishydrogen. In certain embodiments, L¹ is 5 to 15 consecutive covalentlybonded atoms in length. In certain embodiments, R^(H) is a group offormula:

In certain embodiments of Formula (II-f) provided is a compound ofFormula (II-f1):

or a pharmaceutically acceptable salt thereof. In certain embodiments ofFormula (II-f1), c is 0 and R^(A) is absent. In certain embodiments, cis 1, and R^(A) is present, either at the 2 or 3 position from the pointof attachment of the pyrrolidinyl group to the pyrazolyl ring. Incertain embodiments, the group L¹-R^(H) is present either at the 2 or 3position from the point of attachment of the pyrrolidinyl group to thepyrazolyl ring. In certain embodiments, b is 0. In certain embodiments,b is 1, L² is a bond, and R^(D) is a group of Formula (i-1). In certainembodiments, each instance of R^(B) is hydrogen. In certain embodiments,L¹ is 5 to 15 consecutive covalently bonded atoms in length. In certainembodiments, R^(H) is a group of formula:

In certain embodiments, wherein Ring A is substituted or unsubstitutedpiperidinylene, provided is a compound of Formula (II-g):

or a pharmaceutically acceptable salt thereof,wherein:

each occurrence of R^(A) is, independently, hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —C(═O)R^(A1), or—C(═O)OR^(A1), wherein each occurrence of R^(A1) is independentlyhydrogen, acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(A1)groups are joined to form an substituted or unsubstituted heterocyclicor substituted or unsubstituted heteroaryl ring; and

c is 0 or 1.

In certain embodiments of Formula (II-g), c is 0, and R^(A) is absent.In certain embodiments, c is 1 and R^(A) is present, either at the 2, 3,or 4 position from the point of attachment of the piperidinylene groupto the pyrazolyl ring. In certain embodiments, the group L¹-R^(H) ispresent either at the 2, 3, or 4 position from the point of attachmentof the piperidinylene group to the pyrazolyl ring. In certainembodiments, b is 0. In certain embodiments, b is 1, L² is a bond, andR^(D) is a group of Formula (i-1). In certain embodiments, each instanceof R^(B) is hydrogen. In certain embodiments, L¹ is 5 to 15 consecutivecovalently bonded atoms in length. In certain embodiments, R^(H) is agroup of formula:

For example, in certain embodiments of Formula (II-g) provided is acompound of Formula (II-g1):

or a pharmaceutically acceptable salt thereof. In certain embodiments ofFormula (II-g1), c is 0, and R^(A) is absent. In certain embodiments, cis 1, and R^(A) is present, either at the 2 or 3 position from the pointof attachment of the piperidinylene group to the pyrazolyl ring. Incertain embodiments, the group L¹-R^(H) is present either at the 2 or 3position from the point of attachment of the piperidinylene group to thepyrazolyl ring. In certain embodiments, b is 0. In certain embodiments,b is 1, L² is a bond, and R^(D) is a group of Formula (i-1). In certainembodiments, each instance of R^(B) is hydrogen. In certain embodiments,L¹ is 5 to 15 consecutive covalently bonded atoms in length. In certainembodiments, R^(H) is a group of formula:

Non-limiting examples of compounds of Formula (I) and (II), andpharmaceutically acceptable salts, thereof are provided below in Table1.

TABLE 1 Structure

TX2-120-1

TX2-112-1 MW_(total) = 674 g/mol MW(-L¹-R^(H)) = 220 g/mol MW(M − H) =455 g/mol L¹ = 5 atoms long

TX2-126-1 MW_(total) = 757 g/mol MW(-L¹-R^(H)) = 262 g/mol MW(M − H) =496 g/mol L¹ = 7 atoms

(R)-TX2-126-1

(S)-TX2-126-1

TX2-113-1 MW_(total) = 688 g/mol MW(-L¹-R^(H)) = 234 g/mol MW(M − H) =455 g/mol L¹ = 6 atoms long

TX2-121-1 MW_(total) = 716 g/mol MW(-L¹-R^(H)) = 262 g/mol MW(M − H) =455 g/mol L¹ = 7 atoms long

(R)-TX2-121-1

(S)-TX2-121-1

TX2-121-3 MW_(total) = 718 g/mol MW(-L¹-R^(H)) = 262 g/mol MW(M − H) =457 g/mol L¹ = 7 atoms long

(R)-TX2-121-3

(S)-TX2-121-3

TX2-114-1 MW_(total) = 718 g/mol MW(-L¹-R^(H)) = 264 g/mol MW(M − H) =455 g/mol L¹ = 8 atoms long

SML-11-124-1 MW_(total) = 841 g/mol MW(-L¹-R^(H)) = 346 g/mol MW(M −H) =495 g/mol L¹ = 11 atoms long

(R)-SML-11-124-1

(S)-SML-11-124-1

Pharmaceutical Compositions

In certain embodiments, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) or (II) or apharmaceutically acceptable salt thereof and, optionally, apharmaceutically acceptable excipient. In certain embodiments, thecompound is present in an effective amount, e.g., a therapeuticallyeffective amount or a prophylactically effective amount.

Pharmaceutically acceptable excipients include any and all solvents,diluents or other liquid vehicles, dispersion or suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. General considerations in theformulation and/or manufacture of pharmaceutical compositions agents canbe found, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21^(st) Edition(Lippincott Williams & Wilkins, 2005).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of Formula (I) or(II) or a pharmaceutically acceptable salt thereof (the “activeingredient”) into association with the excipient and/or one or moreother accessory ingredients, and then, if necessary and/or desirable,shaping and/or packaging the product into a desired single- ormulti-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable carrier, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, etc., and combinationsthereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, etc., and combinations thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g. acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]),long chain amino acid derivatives, high molecular weight alcohols (e.g.stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate,ethylene glycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acidesters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20],polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate[Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate[Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitanmonooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylenemonostearate [Myrj 45], polyoxyethylene hydrogenated castor oil,polyethoxylated castor oil, polyoxymethylene stearate, and Solutol),sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.,Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether[Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate,triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate,oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68,Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride,benzalkonium chloride, docusate sodium, etc. and/or combinationsthereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, etc., and/or combinations thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, etc., and combinations thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, andcombinations thereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and combinations thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may comprise buffering agents.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. Solid compositions of asimilar type can be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active ingredients can be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier and/or any needed preservativesand/or buffers as can be required. Additionally, the present inventioncontemplates the use of transdermal patches, which often have the addedadvantage of providing controlled delivery of an active ingredient tothe body. Such dosage forms can be prepared, for example, by dissolvingand/or dispensing the active ingredient in the proper medium.Alternatively or additionally, the rate can be controlled by eitherproviding a rate controlling membrane and/or by dispersing the activeingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil in water and/or water in oil emulsions such as creams,ointments and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration may further comprise one or more of the additionalingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

The formulations described herein as being useful for pulmonary deliveryare useful for intranasal delivery of a pharmaceutical composition ofthe invention. Another formulation suitable for intranasaladministration is a coarse powder comprising the active ingredient andhaving an average particle from about 0.2 to 500 micrometers. Such aformulation is administered, by rapid inhalation through the nasalpassage from a container of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) and as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition of the invention can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.1/1.0% (w/w) solution and/or suspension of the activeingredient in an aqueous or oily liquid carrier. Such drops may furthercomprise buffering agents, salts, and/or one or more other of theadditional ingredients described herein. Other opthalmicallyadministrable formulations which are useful include those which comprisethe active ingredient in microcrystalline form and/or in a liposomalpreparation. Ear drops and/or eye drops are contemplated as being withinthe scope of this invention.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.General considerations in the formulation and/or manufacture ofpharmaceutical compositions can be found, for example, in Remington: TheScience and Practice of Pharmacy 21^(st) ed., Lippincott Williams &Wilkins, 2005.

Still further encompassed by the invention are pharmaceutical packsand/or kits. Pharmaceutical packs and/or kits provided may comprise aprovided composition and a container (e.g., a vial, ampoule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a suitable aqueous carrier for dilution orsuspension of the provided composition for preparation of administrationto a subject. In some embodiments, contents of provided formulationcontainer and solvent container combine to form at least one unit dosageform.

Optionally, a single container may comprise one or more compartments forcontaining a provided composition, and/or appropriate aqueous carrierfor suspension or dilution. In some embodiments, a single container canbe appropriate for modification such that the container may receive aphysical modification so as to allow combination of compartments and/orcomponents of individual compartments. For example, a foil or plasticbag may comprise two or more compartments separated by a perforated sealwhich can be broken so as to allow combination of contents of twoindividual compartments once the signal to break the seal is generated.A pharmaceutical pack or kit may thus comprise such multi-compartmentcontainers including a provided composition and appropriate solventand/or appropriate aqueous carrier for suspension.

Optionally, instructions for use are additionally provided in such kitsof the invention. Such instructions may provide, generally, for example,instructions for dosage and administration. In other embodiments,instructions may further provide additional detail relating tospecialized instructions for particular containers and/or systems foradministration. Still further, instructions may provide specializedinstructions for use in conjunction and/or in combination withadditional therapy.

Methods of Treatment

The present invention also provides methods of using the compounds ofFormula (I) or (II) as described herein for treating a conditionassociated with aberrant activity of a kinase. “Aberrant activity” of akinase refers to any undesired activity, and includes, but is notlimited to, over-activity and/or over-expression of the kinase comparedto a normal cell. Such methods include therapeutic as well asprophylactic (preventative) methods.

For example, in one aspect, provided is a method of treating a conditionassociated with aberrant activity of a kinase, the method comprisingadministering an effective amount of a compound of Formula (I) or (II),or pharmaceutical composition thereof, to a subject in need thereof inan amount sufficient to reduce kinase activity.

In certain embodiments, the compound reduces or prevents kinase activityby targeted degradation of the kinase. In certain embodiments, thecompound reduces kinase activity by inducing unfolding of the kinase. Incertain embodiments, the compound reduces kinase activity by inducingdegradation of the kinase. In certain embodiments, the compound reduceskinase activity by covalently binding to the kinase. In certainembodiments, compound reduces kinase activity by non-covalently bindingto the kinase.

Exemplary conditions associated with aberrant activity of a kinaseincludes, but are not limited to, proliferative disorders, inflammatorydisorders, autoimmune disorders, painful conditions, metabolicdisorders, CNS disorders, and viral infections.

In certain embodiments, the condition associated with aberrant activityof a kinase is a proliferative disorder. Exemplary proliferativediseases include, but are not limited to, tumors, begnin neoplasms,pre-malignant neoplasms (carcinoma in situ), and malignant neoplasms(cancers).

Exemplary cancers include, but are not limited to, acoustic neuroma,adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g.,lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma),appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g.,cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinomaof the breast, papillary carcinoma of the breast, mammary cancer,medullary carcinoma of the breast), brain cancer (e.g., meningioma;glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchuscancer, carcinoid tumor, cervical cancer (e.g., cervicaladenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma,colorectal cancer (e.g., colon cancer, rectal cancer, colorectaladenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma(e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma),endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophagealcancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma),Ewing's sarcoma, eye cancer (e.g., intraocular melanoma,retinoblastoma), familiar hypereosinophilia, gall bladder cancer,gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromaltumor (GIST), head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC),throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma suchas Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkinlymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma(DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., “Waldenström's macroglobulinemia”), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphomalleukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma (MM)), heavy chain disease (e.g.,alpha chain disease, gamma chain disease, mu chain disease),hemangioblastoma, inflammatory myofibroblastic tumors, immunocyticamyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor,renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC),malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, smallcell lung cancer (SCLC), non-small cell lung cancer (NSCLC),adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g.,systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma,myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV),essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocyticleukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilicsyndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis(NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g.,gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoidtumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarianembryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma,pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductalpapillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer(e.g., Paget's disease of the penis and scrotum), pinealoma, primitiveneuroectodermal tumor (PNT), prostate cancer (e.g., prostateadenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer,skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g.,appendix cancer), soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous glandcarcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g.,seminoma, testicular embryonal carcinoma), thyroid cancer (e.g.,papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC),medullary thyroid cancer), urethral cancer, vaginal cancer and vulvarcancer (e.g., Paget's disease of the vulva).

In certain embodiments, the condition associated with aberrant activityof a kinase is an inflammatory disorder. The term “inflammatorydisorder” refers to those diseases, disorders or conditions that arecharacterized by signs of pain (dolor, from the generation of noxioussubstances and the stimulation of nerves), heat (calor, fromvasodilatation), redness (rubor, from vasodilatation and increased bloodflow), swelling (tumor, from excessive inflow or restricted outflow offluid), and/or loss of function (functio laesa, which can be partial orcomplete, temporary or permanent. Inflammation takes on many forms andincludes, but is not limited to, acute, adhesive, atrophic, catarrhal,chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous,fibrosing, focal, granulomatous, hyperplastic, hypertrophic,interstitial, metastatic, necrotic, obliterative, parenchymatous,plastic, productive, proliferous, pseudomembranous, purulent,sclerosing, seroplastic, serous, simple, specific, subacute,suppurative, toxic, traumatic, and/or ulcerative inflammation.

Exemplary inflammatory disorders include, but are not limited to,inflammation associated with acne, anemia (e.g., aplastic anemia,haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthritis, psoriaticarthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis andReiter's arthritis), ankylosing spondylitis, amylosis, amyotrophiclateral sclerosis, autoimmune diseases, allergies or allergic reactions,atherosclerosis, bronchitis, bursitis, chronic prostatitis,conjunctivitis, Chagas disease, chronic obstructive pulmonary disease,cermatomyositis, diverticulitis, diabetes (e.g., type I diabetesmellitus, type 2 diabetes mellitus), a skin condition (e.g., psoriasis,eczema, burns, dermatitis, pruritus (itch)), endometriosis,Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasakidisease, glomerulonephritis, gingivitis, hypersensitivity, headaches(e.g., migraine headaches, tension headaches), ileus (e.g.,postoperative ileus and ileus during sepsis), idiopathicthrombocytopenic purpura, interstitial cystitis (painful bladdersyndrome), gastrointestinal disorder (e.g., selected from peptic ulcers,regional enteritis, diverticulitis, gastrointestinal bleeding,eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, orits synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn'sdisease, ulcerative colitis, collagenous colitis, lymphocytic colitis,ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminatecolitis) and inflammatory bowel syndrome (IBS)), lupus, multiplesclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephroticsyndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers,polymyositis, primary biliary cirrhosis, neuroinflammation associatedwith brain disorders (e.g., Parkinson's disease, Huntington's disease,and Alzheimer's disease), prostatitis, chronic inflammation associatedwith cranial radiation injury, pelvic inflammatory disease, reperfusioninjury, regional enteritis, rheumatic fever, systemic lupuserythematosus, schleroderma, scierodoma, sarcoidosis,spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantationrejection, tendonitis, trauma or injury (e.g., frostbite, chemicalirritants, toxins, scarring, burns, physical injury), vasculitis,vitiligo and Wegener's granulomatosis.

In certain embodiments, the inflammatory disorder is inflammationassociated with a proliferative disorder, e.g., inflammation associatedwith cancer.

In certain embodiments, the condition associated with aberrant activityof a kinase is an autoimmune disorder. Exemplary autoimmune disordersinclude, but are not limited to, arthritis (including rheumatoidarthritis, spondyloarthopathies, gouty arthritis, degenerative jointdiseases such as osteoarthritis, systemic lupus erythematosus, Sjogren'ssyndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet'sdisease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophiclateral sclerosis, amylosis, acute painful shoulder, psoriatic, andjuvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns,dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrointestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), and disorders ameliorated by agastroprokinetic agent (e.g., ileus, postoperative ileus and ileusduring sepsis; gastroesophageal reflux disease (GORD, or its synonymGERD); eosinophilic esophagitis, gastroparesis such as diabeticgastroparesis; food intolerances and food allergies and other functionalbowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiacchest pain (NCCP, including costo-chondritis)).

In certain embodiments, the condition associated with aberrant activityof a kinase is a painful condition. A “painful condition” includes, butis not limited to, neuropathic pain (e.g., peripheral neuropathic pain),central pain, deafferentiation pain, chronic pain (e.g., chronicnociceptive pain, and other forms of chronic pain such as post-operativepain, e.g., pain arising after hip, knee, or other replacement surgery),pre-operative pain, stimulus of nociceptive receptors (nociceptivepain), acute pain (e.g., phantom and transient acute pain),noninflammatory pain, inflammatory pain, pain associated with cancer,wound pain, burn pain, postoperative pain, pain associated with medicalprocedures, pain resulting from pruritus, painful bladder syndrome, painassociated with premenstrual dysphoric disorder and/or premenstrualsyndrome, pain associated with chronic fatigue syndrome, pain associatedwith pre-term labor, pain associated with withdrawl symptoms from drugaddiction, joint pain, arthritic pain (e.g., pain associated withcrystalline arthritis, osteoarthritis, psoriatic arthritis, goutyarthritis, reactive arthritis, rheumatoid arthritis or Reiter'sarthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine,muscle ache, lower back pain, neck pain, toothache, dental/maxillofacialpain, visceral pain and the like. One or more of the painful conditionscontemplated herein can comprise mixtures of various types of painprovided above and herein (e.g. nociceptive pain, inflammatory pain,neuropathic pain, etc.). In some embodiments, a particular pain candominate. In other embodiments, the painful condition comprises two ormore types of pains without one dominating. A skilled clinician candetermine the dosage to achieve a therapeutically effective amount for aparticular subject based on the painful condition.

In certain embodiments, the painful condition is inflammatory pain. Incertain embodiments, the painful condition (e.g., inflammatory pain) isassociated with an inflammatory disorder and/or an autoimmune disorder.

In certain embodiments, the condition associated with aberrant activityof a kinase is a metabolic disorder (e.g., a wasting condition, anobesity-related condition or complication thereof).

In certain embodiments, the metabolic disorder is a wasting condition. A“wasting condition,” as used herein, includes but is not limited to,anorexia and cachexias of various natures (e.g., weight loss associatedwith cancer, weight loss associated with other general medicalconditions, weight loss associated with failure to thrive, and thelike). In certain embodiments, the metabolic disorder is anobesity-related condition or a complication thereof. An “obesity-relatedcondition” as used herein, includes, but is not limited to, obesity,undesired weight gain (e.g., from medication-induced weight gain, fromcessation of smoking) and an over-eating disorder (e.g., binge eating,bulimia, compulsive eating, or a lack of appetite control each of whichcan optionally lead to undesired weight gain or obesity). “Obesity” and“obese” as used herein, refers to class I obesity, class II obesity,class III obesity and pre-obesity (e.g., being “over-weight”) as definedby the World Health Organization.

In certain embodiments, the condition associated with aberrant activityof a kinase is a CNS disorder. Exemplary CNS disorders include, but arenot limited to, neurotoxicity and/or neurotrauma, stroke, multiplesclerosis, spinal cord injury, epilepsy, a mental disorder, a sleepcondition, a movement disorder, nausea and/or emesis, amyotrophiclateral sclerosis, Alzheimer's disease and drug addiction.

In certain embodiments, the CNS disorder is neurotoxicity and/orneurotrauma, e.g., for example, as a result of acute neuronal injury(e.g., tramatic brain injury (TBI), stroke, epilepsy) or a chronicneurodegenerative disorder (e.g., multiple sclerosis, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis,Alzheimer's disease).

In certain embodiments, the CNS disorder is a mental disorder, e.g., forexample, depression, anxiety or anxiety-related conditions, a learningdisability or schizophrenia.

In certain embodiments, the CNS disorder is depression. “Depression,” asused herein, includes, but is not limited to, depressive disorders orconditions, such as, for example, major depressive disorders (e.g.,unipolar depression), dysthymic disorders (e.g., chronic, milddepression), bipolar disorders (e.g., manic-depression), seasonalaffective disorder, and/or depression associated with drug addiction(e.g., withdrawal). The depression can be clinical or subclinicaldepression. The depression can be associated with or premenstrualsyndrome and/or premenstrual dysphoric disorder.

In certain embodiments, the CNS disorder is anxiety. “Anxiety,” as usedherein, includes, but is not limited to anxiety and anxiety-relatedconditions, such as, for example, clinical anxiety, panic disorder,agoraphobia, generalized anxiety disorder, specific phobia, socialphobia, obsessive-compulsive disorder, acute stress disorder,post-traumatic stress disorder, adjustment disorders with anxiousfeatures, anxiety disorder associated with depression, anxiety disorderdue to general medical conditions, and substance-induced anxietydisorders, anxiety associated with drug addiction (e.g., withdrawal,dependence, reinstatement) and anxiety associated with nausea and/oremesis. This treatment may also be to induce or promote sleep in asubject (e.g., for example, a subject with anxiety).

In certain embodiments, the CNS disorder is a learning disorder (e.g.,attention deficit disorder (ADD)).

In certain embodiments, the CNS disorder is Schizophrenia.

In certain embodiments, the CNS disorder is a sleep condition. “Sleepconditions” include, but are not limited to, insomnia, narcolepsy, sleepapnea, restless legs syndrome (RLS), delayed sleep phase syndrome(DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapideye movement behavior disorder (RBD), shift work sleep condition (SWSD),and sleep problems (e.g., parasomnias) such as nightmares, nightterrors, sleep talking, head banging, snoring, and clenched jaw and/orgrinding of teeth (bruxism).

In certain embodiments, the CNS disorder is a movement disorder, e.g.,basal ganglia disorders, such as, for example, Parkinson's disease,levodopa-induced dyskinesia, Huntington's disease, Gilles de IaTourette's syndrome, tardive diskinesia and dystonia.

In certain embodiments, the CNS disorder is Alzheimer's disease.

In certain embodiments, the CNS disorder is amyotrophic lateralsclerosis (ALS).

In certain embodiments, the CNS disorder is nausea and/or emesis.

In certain embodiments, the CNS disorder is drug addiction (e.g., forinstance, addiction to opiates, nicotine, cocaine, psychostimulants oralcohol).

In certain embodiments, the condition associated with aberrant activityof a kinase is a viral infection.

In certain embodiments of Formula (I) and (II), the kinase is Her3protein kinase. In this instance, in certain embodiments, the conditionassociated with aberrant activity of Her3 protein kinase is aproliferative disorder. In certain embodiments, the proliferativedisorder associated with aberrant activity of Her3 protein kinase iscancer. In certain embodiments, the cancer associated with aberrantactivity of Her3 protein kinase is breast cancer, lung cancer, orovarian cancer. In certain embodiments, the breast cancer associatedwith aberrant activity of Her3 protein kinase is Her2 driven breastcancer. In certain embodiments, the lung cancer associated with aberrantactivity of Her3 protein kinase is gefitinib resistant lung cancer. Incertain embodiments, the lung cancer is NSCLC.

Compounds of Formula (I) or (II) may be formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionscomprising a compound of Formula (I) or (II) will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular subjector organism will depend upon a variety of factors including the disease,disorder, or condition being treated and the severity of the disorder;the activity of the specific active ingredient employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the subject; the time of administration, route of administration, andrate of excretion of the specific active ingredient employed; theduration of the treatment; drugs used in combination or coincidentalwith the specific active ingredient employed; and like factors wellknown in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),the condition of the subject (e.g., whether the subject is able totolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the compounds of the invention may beadministered orally or parenterally at dosage levels sufficient todeliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kgto about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg,preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kgto about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and morepreferably from about 1 mg/kg to about 25 mg/kg, of subject body weightper day, one or more times a day, to obtain the desired therapeuticeffect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compounds or compositions can beadministered in combination with additional therapeutically activeagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body. It will also be appreciated that the therapy employedmay achieve a desired effect for the same disorder (for example, acompound can be administered in combination with an anti-inflammatoryagent, anti-cancer agent, etc.), and/or it may achieve different effects(e.g., control of adverse side-effects, e.g., emesis controlled by ananti-emetic).

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional therapeutically activeagents. In general, each agent will be administered at a dose and/or ona time schedule determined for that agent. In will further beappreciated that the additional therapeutically active agent utilized inthis combination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the inventive compound with the additional therapeutically activeagent and/or the desired therapeutic effect to be achieved. In general,it is expected that additional therapeutically active agents utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually.Additional therapeutically active agents include, but are not limitedto, small organic molecules such as drug compounds (e.g., compoundsapproved by the Food and Drugs Administration as provided in the Code ofFederal Regulations (CFR)), peptides, proteins, carbohydrates,monosaccharides, oligosaccharides, polysaccharides, nucleoproteins,mucoproteins, lipoproteins, synthetic polypeptides or proteins, smallmolecules linked to proteins, glycoproteins, steroids, nucleic acids,DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisenseoligonucleotides, lipids, hormones, vitamins and cells. In certainembodiments, the additional therapeutically agent is a cancer agent(e.g., a biotherapeutic or chemotherapeutic cancer agent). In otherembodiments, the additional therapeutically active agent is ananti-inflammatory agent.

Methods of Preparation

Compounds of the present invention may be prepared by coupling acompound substituted with a group -L³-X* with a compound of formulaY*-L⁴-R^(H), wherein X* and Y* react together to form a group A, thusproviding a compound substituted with a group of formula -L³-A-L⁴-R^(H).It should be understood that the group of formula -L³-A-L⁴- isencompassed by the group of formula -L¹- as defined herein.

It should also be understood that, for a compound of Formula (P-I) or(P-II), the group Y* of the compound of formula Y*-L⁴-R^(H), should becomplimentary and reactive with the group X* present on the precursorcompound in order to form the compound of Formula (I″) or (II″). Forexample, if the group Y* is a nucleophilic group, the group X* must be aelectrophilic group. Likewise, if the group Y* is an electrophilicgroup, the group X* must be a nucleophilic group. While X* and Y* aredefined the same in the present invention, it is thus understood thatsuch groups are paired compliments.

In certain embodiments, the coupling of a compound substituted with agroup -L³-X* with a compound of formula Y*-L⁴-R^(H) is via “clickchemistry.” Click chemistry is a chemical philosophy introduced bySharpless in 2001 and describes chemistry tailored to generatesubstances quickly and reliably by joining small units together. See,e.g., Kolb, Finn and Sharpless, Angewandte Chemie International Edition(2001) 40: 2004-2021; Evans, Australian Journal of Chemistry (2007) 60:384-395. Exemplary coupling reactions (some of which may be classifiedas “click chemistry”) include, but are not limited to, formation ofesters, thioesters, amides (e.g., such as peptide coupling) fromactivated acids or acyl halides; nucleophilic displacement reactions(e.g., such as nucleophilic displacement of a halide or ring opening ofstrained ring systems); azide-alkyne Huisgen cycloaddition; thiol-yneaddition; imine formation; and Michael additions (e.g., maleimideaddition).

In any of the above and below embodiments, L³ and L⁴ represent a bond ora linker selected from the group consisting of substituted andunsubstituted alkylene; substituted and unsubstituted alkenylene;substituted and unsubstituted alkynylene; substituted and unsubstitutedheteroalkylene; substituted and unsubstituted heteroalkenylene;substituted and unsubstituted heteroalkynylene; substituted andunsubstituted heterocyclylene; substituted and unsubstitutedcarbocyclylene; substituted and unsubstituted arylene; substituted andunsubstituted heteroarylene; and combinations thereof. Groups of formulaA, X*, and Y* are further defined herein.

In any of the embodiments herein, X* and Y* independently represent agroup —SH, —OH, —NH₂, —NH—NH₂, —N₃, —O—NH₂, halogen (or other leavinggroup),

wherein:

R^(X1) is hydrogen, halogen, or —OR^(X2), wherein R^(X2) is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkyl;substituted or unsubstituted alkenyl; substituted or unsubstitutedalkynyl; substituted or unsubstituted heteroalkyl; substituted orunsubstituted heteroalkenyl; substituted or unsubstituted heteroalkynyl;substituted or unsubstituted carbocyclyl; substituted or unsubstitutedheterocyclyl; substituted or unsubstituted aryl; substituted orunsubstituted heteroaryl; or an oxygen protecting group;

W is O, S, or NR^(W1);

R^(W1) is hydrogen, substituted or unsubstituted alkyl; substituted orunsubstituted alkenyl; substituted or unsubstituted alkynyl; substitutedor unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl; or a nitrogen protecting group; and

R^(W2) is hydrogen, substituted or unsubstituted alkyl; substituted orunsubstituted alkenyl; substituted or unsubstituted alkynyl; substitutedor unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; or substituted or unsubstitutedheteroaryl, or two R^(W2) groups are joined to form a 5-6 membered ring.

In certain embodiments, Y* is —SH. In certain embodiments, X* is —SH.

In certain embodiments, Y* is —OH. In certain embodiments, X* is —OH.

In certain embodiments, Y* is —NH₂. In certain embodiments, X* is —NH₂.

In certain embodiments, Y* is —NH—NH₂. In certain embodiments, X* is—NH—NH₂.

In certain embodiments, Y* is —O—NH₂. In certain embodiments, X* is—O—NH₂.

In certain embodiments, Y* is —N₃. In certain embodiments, X* is —N₃.

In certain embodiments, Y* is halogen, e.g., —Cl, —Br, or —I. In certainembodiments, X* is halogen, e.g., —Cl, —Br, or —I.

In certain embodiments, Y* is —C(═O)R^(X1), wherein R^(X1) is hydrogen,i.e., to provide Y* as an aldehyde —CHO. In certain embodiments, X* is—C(═O)R^(X1), wherein R^(X1) is hydrogen, i.e., to provide X* as analdehyde —CHO.

In certain embodiments, Y* is —C(═O)R^(X1), wherein R^(X1) is halogen(e.g., “Hal” representing —Cl, —Br, and —I), i.e., to provide Y* as anacyl halide —C(═O)—Hal.

In certain embodiments, X* is —C(═O)R^(X1), wherein R^(X1) is halogen(e.g., “Hal” representing —Cl, —Br, and —I), i.e., to provide X* as anacyl halide —C(═O)—Hal.

In certain embodiments, Y* is —C(═O)R^(X1), wherein R^(X1) is —OR^(X2),and wherein R^(X2) is hydrogen, i.e., to provide Y* as a carboxylic acid—C(═O)OH.

In certain embodiments, X* is —C(═O)R^(X1), wherein R^(X1) is —OR^(X2),and wherein R^(X2) is hydrogen, i.e., to provide X* as a carboxylic acid—C(═O)OH.

In certain embodiments, Y* is —C(═O)R^(X1), wherein R^(Z1) is —OR^(X2),and wherein R^(X2) is substituted or unsubstituted alkyl; substituted orunsubstituted alkenyl; substituted or unsubstituted alkynyl; substitutedor unsubstituted heteroalkyl; substituted or unsubstitutedheteroalkenyl; substituted or unsubstituted heteroalkynyl; substitutedor unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl; or an oxygen protecting group, i.e., to provide Y* as anester —C(═O)OR^(X2)

In certain embodiments, X* is —C(═O)R^(X1), wherein R^(Z1) is —OR^(X2),and wherein R^(X2) is substituted or unsubstituted alkyl; substituted orunsubstituted alkenyl; substituted or unsubstituted alkynyl; substitutedor unsubstituted heteroalkyl; substituted or unsubstitutedheteroalkenyl; substituted or unsubstituted heteroalkynyl; substitutedor unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl; or an oxygen protecting group, i.e., to provide X* as anester —C(═O)OR^(X2)

In certain embodiments, X* or Y* is an oxiranyl of formula:

In certain embodiments, X* or Y* is ethynyl:

In certain embodiments, X* or Y* is ethenyl:

In certain embodiments, X* or Y* is an α,β-unsaturated carbonyl:

In certain embodiments, X* or Y* is a maleimide group:

Furthermore, as generally understood herein, X* and Y* may reacttogether to form a group A, wherein A is a group of the formula:

wherein:

Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—, —O—;

W is O, S, or NR^(W1);

R^(W1) is hydrogen, substituted or unsubstituted alkyl; substituted orunsubstituted alkenyl; substituted or unsubstituted alkynyl; substitutedor unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl; a nitrogen protecting group if attached to a nitrogen atom,or an oxygen group if attached to an oxygen atom; and

R^(W2) is hydrogen, substituted or unsubstituted alkyl; substituted orunsubstituted alkenyl; substituted or unsubstituted alkynyl; substitutedor unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl, or two R^(W2) groups are joined to form a 5-6 membered ring;

In certain embodiments, A is —NH—.

In certain embodiments, A is —NH—NH—.

In certain embodiments, A is —S—.

In certain embodiments, A is —O—.

In certain embodiments, A is a disulfide group

In certain embodiments, A is

wherein Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—, —O—. For example, incertain embodiments, wherein Q is —NH—, A is an amide group of theformula

In certain embodiments, wherein Q is —NH—NH—, A is an amide hydrazidegroup of the formula

In certain embodiments, wherein Q is —S—, A is an thioester group of theformula

In certain embodiments, wherein Q is —O—, A is an ester group of theformula

In certain embodiments, A is

In certain embodiments, R^(W2) is alkyl, e.g., methyl.

In certain embodiments, A is

In certain embodiments, R^(W2) is alkyl, e.g., methyl. In certainembodiments, R^(W1) is hydrogen.

In certain embodiments, A is

In certain embodiments, R^(W2) is alkyl, e.g., methyl.

In certain embodiments, A is:

In certain embodiments, A is:

wherein R^(W1) is hydrogen, substituted or unsubstituted alkyl, or anamino protecting group; and Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—,—O—. In certain embodiments, Q is —NH—. In certain embodiments, Q is—NH—NH—. In certain embodiments, Q is —S—. In certain embodiments, Q is—O—.

In certain embodiments, A is:

wherein Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—, or —O—. In certainembodiments, Q is —NH—. In certain embodiments, Q is —NH—NH—. In certainembodiments, Q is —S—. In certain embodiments, Q is —O—.

In certain embodiments, A is:

wherein Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—, or —O—. In certainembodiments, Q is —NH—. In certain embodiments, Q is —NH—NH—. In certainembodiments, Q is —S—. In certain embodiments, Q is —O—.

In certain embodiments, A is:

wherein W is O, S, or NR^(W1), R^(W1) is hydrogen, substituted orunsubstituted alkyl, or an amino protecting group; and Q is —NH—,—NH—NH—, —O—NH—, —NH—O—, —S—, or —O—. In certain embodiments, W is O. Incertain embodiments, W is S. In certain embodiments, W is NR^(W1). Incertain embodiments, Q is —NH—. In certain embodiments, Q is —NH—NH—. Incertain embodiments, Q is —S—. In certain embodiments, Q is —O—.

In one aspect, provided is a method of preparing a compound of Formula(I″) or (II″), or pharmaceutically acceptable salt thereof, the methodcomprising coupling of a precursor compound of Formula (P-I) or (P-II)or pharmaceutically acceptable salt thereof with a compound of formulaY*-L⁴-R^(H)

In certain embodiments, the method of preparing a compound of Formula(I″) or (II″), or pharmaceutically acceptable salt thereof, comprisescoupling a precursor compound of Formula (P-I) or (P-II), orpharmaceutically acceptable salt thereof, with a compound of formulaY*-L⁴-R^(H), wherein one of X* and Y* is —C(═O)R^(X1), wherein R^(X1) ishalogen or —OR^(X2) and one of X* and Y* is —SH, —OH, —NH₂, or —NH—NH₂to provide a compound of Formula (I″) or (II″), wherein A is an amide,thioester, or ester group. See, e.g., Table 2.

TABLE 2 R^(X1) Y* X* A —C(═O)Q—, —QC(═O)— halogen or —OR^(X2) —SH—C(═O)S— —SH —SC(═O)— —OH —C(═O)O— —OH —OC(═O)— —NH₂ —C(═O)NH— —NH₂—NHC(═O)— —NH—NH₂ —C(═O)NHNH— —NH—NH₂ —NHNHC(═O)—

In certain embodiments, the method of preparing a compound of Formula(I″) or (II″), or pharmaceutically acceptable salt thereof, comprisescoupling a precursor compound of Formula (P-I) or (P-II), orpharmaceutically acceptable salt thereof, with a compound of formulaY*-L⁴-R^(H), wherein one of X* and Y* is halogen or another leavinggroup, and one of X* and Y* is —SH, —OH, —NH₂, or —NH—NH₂ to provide acompound of Formula (I′) or (II′), wherein A is, respectively, —S—, —O—,—NH—, or —NH—NH—. See, e.g., Table 3.

TABLE 3 Y* X* A Hal or other leaving group —SH —S— —OH —O— —NH₂ —NH——NH—NH₂ —NH—NH— —O—NH₂ —O—NH— —SH Hal or other leaving group —S— —OH —O——NH₂ —NH— —NH—NH₂ —NH—NH— —O—NH₂ —NH—O—

In certain embodiments, the method of preparing a compound of Formula(I″) or (II″), or pharmaceutically acceptable salt thereof, comprisescoupling (azide-alkyne Huisgen cycloaddition of) a precursor compound ofFormula (P-I) or (P-II), or pharmaceutically acceptable salt thereof,with a compound of formula Y*-L⁴-R^(H), wherein one of X* and Y* is

and one of X* and Y* is —N₃. See, e.g., Table 4.

TABLE 4 A X* Y* 1,4-adduct 1,5-adduct — —N₃

—N₃ —

In certain embodiments, the method of preparing a compound of Formula(I″) or (II″), or pharmaceutically acceptable salt thereof, comprisescoupling (via thiol-yne addition of) a precursor compound of Formula(P-I) or (P-II), or pharmaceutically acceptable salt thereof, with acompound of formula Y*-L⁴-R^(H), wherein one of X* and Y* is

and one of X* and Y* is —SH. See, e.g., Table 5.

TABLE 5 X* Y* A — —SH

—SH —

In certain embodiments, the method of preparing a compound of Formula(I″) or (II″), or pharmaceutically acceptable salt thereof, comprisescoupling a precursor compound of Formula (P-I) or (P-II), orpharmaceutically acceptable salt thereof, with a compound of formulaY*-L⁴-R^(H), wherein one of X* and Y* is an aldehyde —CHO or ketone, andone of X* and Y* is —NH₂, —NH—NH₂, or —O—NH₂. See, e.g., Table 6.

TABLE 6 X* Y* A — —NH₂

— —NH—NH₂

— —O—NH₂

—NH₂ —

—NH—NH₂ —

—O—NH₂ —

In certain embodiments, the method of preparing a compound of Formula(I″) or (II″), or pharmaceutically acceptable salt thereof, comprisescoupling a precursor compound of Formula (P-I) or (P-II), orpharmaceutically acceptable salt thereof, with a compound of formulaY*-L⁴-R^(H), wherein one of X* and Y* is an α,β-unsaturated carbonyl,and one of X* and Y* is —OH, —SH, —NH₂, —NHNH₂, or —O—NH₂. See, e.g.,Table 7.

TABLE 7 X* Y* A

—OH, —SH, —NH₂, —NHNH₂, —O—NH₂

—OH, —SH, —NH₂, —NHNH₂, —O—NH₂

In certain embodiments, the method of preparing a compound of Formula(I′) or (II′) or pharmaceutically acceptable salt thereof comprisescoupling a precursor compound of Formula (P-I) or (P-II) orpharmaceutically acceptable salt thereof with a compound of formulaY*-L⁴-R^(H), wherein one of X* and Y* is a maleimide group, and one ofX* and Y* is —OH, —SH, —NH₂, —NHNH₂, or —O—NH₂. See, e.g., Table 8.

TABLE 8 X* Y* A

—OH, —SH, —NH₂, —NHNH₂, —O—NH₂

—OH, —SH, —NH₂, —NHNH₂, —O—NH₂

—OH, —SH, —NH₂, —NHNH₂, —O—NH₂

—OH, —SH, —NH₂, —NHNH₂, —O—NH₂

In certain embodiments, the method of preparing a compound of Formula(I″) or (II″), or pharmaceutically acceptable salt thereof, comprisescoupling a precursor compound of Formula (P-I) or (P-II), orpharmaceutically acceptable salt thereof, with a compound of formulaY*-L⁴-R^(H), wherein each of X* and Y* is —SH to provide, upon treatmentwith an oxidant, a compound of Formula (I′) or (II′), orpharmaceutically acceptable salt thereof, wherein A is a disulfide(—S—S—) bond.

Examples

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

Synthetic Procedures

Synthesis of Compound (2)

To a suspension of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (1) (2.8 g, 20.7mmol) in DMF (12 mL) was added N-iodosuccinimide (5.59 g, 24.8 mmol) atambient temperature. The reaction mixture was heated to 80° C. andstirred for 14 hr. The resulting solid was collected by filtration,rinsed with ice-cold ethanol (20 mL), and concentrated invacuo toprovide 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.9 g, 72%) as anoff-white solid. MS m/z: 261.92 (M+1).

Synthesis of Compound (3)

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (531.8 mg,2.04 mmol) in THF (12 mL) under argon atmosphere were added1,4-dioxaspiro[4.5]decan-8-ol (826.4 μL, 6.11 mmol), triphenylphosphine(1.07 g, 4.07 mmol) and diisopropyl azodicarboxylate (802.3 μL, 4.07mmol) at ambient temperature in this order. The reaction mixture wasstirred at ambient temperature for 16 hr and concentrated in vacuo. Thecrude mixture was taken up in acetone (15 mL) and 6N HCl (5 mL) wasadded dropwise. The solution was stirred at ambient temperature for 4 hrand concentrated in vacuo. The residue was purified by flash-columnchromatography (5% methanol-dichloromethane) to provide4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone (337.2mg, 46.3%) as a yellow oil. MS m/z: 357.90 (M).

Synthesis of Compound (4)

To a solution of4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone (168.5mg, 0.47 mmol) in 1,2-dichloroethane (2.5 mL) was added tert-butylpiperazine-1-carboxylate (158.2 mg, 0.85 mmol) at 0° C. After 5 min,sodium triacetoxyborohydride (180.0 mg, 0.849 mmol) was added to thereaction mixture which was warmed up to ambient temperature and stirredfor 14 hr. The mixture was diluted with dichloromethane (10 mL), washedwith a saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL)and concentrated invacuo. The residue was purified by flash-columnchromatography (10% methanol-dichloromethane) to providetert-butyl-4-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(89.5 mg, 36.0%) as a white solid. MS m/z: 528.06 (M+1).

Synthesis of Compound (5)

To a solution of4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone (168.5mg, 0.47 mmol) in 1,2-dichloroethane (2.5 mL) was added1-(piperazin-1-yl)ethanone (108.8 mg, 0.85 mmol) at 0° C. After 5 min,sodium triacetoxyborohydride (180.0 mg, 0.849 mmol) was added to thereaction mixture which was warmed up to ambient temperature and stirredfor 14 hr. The mixture was diluted with dichloromethane (10 mL), washedwith a saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL)and concentrated invacuo. The residue was purified by flash-columnchromatography (10% methanol-dichloromethane) tocis-1-(4-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)ethanone(55 mg, 25%). ¹H NMR: (600 MHz, DMSO-d₆) δ (ppm): 8.31 (s, 1H); 6.05 (m,2H); 4.83 (s, 1H); 3.65 (m, 5H); 2.58 (m, 4H); 2.39 (m, 3H); 2.10 (m,8H); MS m/z: 470.36 (M+1).trans-1-(4-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)ethanone(78 mg, 35%). ¹H NMR: (600 MHz, DMSO-d₆) δ (ppm): 8.33 (s, 1H); 6.02 (m,2H); 4.65 (s, 1H); 3.62 (m, 5H); 2.62 (m, 7H); 2.13 (m, 8H); MS m/z:470.36 (M+1). MS m/z: 470.72 (M+1).

Synthesis of Compound (6)

To a solution of4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone (168.5mg, 0.47 mmol) in 1,2-dichloroethane (2.5 mL) was added1-methylpiperazine (85 mg, 0.85 mmol) at 0° C. After 5 min, sodiumtriacetoxyborohydride (180.0 mg, 0.849 mmol) was added to the reactionmixture which was warmed up to ambient temperature and stirred for 14hr. The mixture was diluted with dichloromethane (10 mL), washed with asaturated aqueous sodium bicarbonate (10 mL) and brine (10 mL) andconcentrated in vacuo. The residue was purified by flash-columnchromatography (10% methanol-dichloromethane) to1-(4-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)ethanone(105 mg, 51%). MS m/z: 442.45 (M+1).

Synthesis of Compound (7)

To a solution of tert-butyl4-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(360 mg, 0.68 mmol) in dioxane (6 mL) were added(4-fluoro-3-nitrophenyl)boronic acid (177 mg, 0.96 mmol) and 1M aqueoussolution of sodium carbonate (2 mL) at ambient temperature. Theresulting suspension was degassed with argon for 3 min andbis(triphenylphosphine)palladium(II) dichloride (35 mg, 0.05 mmol) wasadded. The mixture was heated to 80° C. and stirred for 2 hr. It wasdiluted with dichloromethane (30 mL), washed with water (30 mL) andconcentrated in vacuo. The residue was purified by flash-columnchromatography (10% methanol-dichloromethane) to provide tert-butyl4-(4-(4-amino-3-(4-fluoro-3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(312 mg, 85%). MS m/z: 541.75 (M+1).

Synthesis of Compound (8)

To a solution of tert-butyl4-(4-(4-amino-3-(4-fluoro-3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(312 mg, 0.58 mmol) in dimethylformamide (3 ml) were added phenol (81.7mg 0.87 mmol) and potassium carbonate (120 mg, 0.87 mmol) at ambienttemperature. The mixture was heated up to to 80° C. and stirredovernight. Worked up with dichloromethane and water, concentrated invacuo. The residue was purified by flash-column chromatography (10%methanol-dichloromethane) to tert-butyl4-(4-(4-amino-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(268.2 mg 75.4%). MS m/z: 615.49 (M+1).

Synthesis of Compound (9)

To a solution of tert-butyl4-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(234 mg, 0.50 mmol) in dioxane (6 mL) were added(4-fluoro-3-nitrophenyl)boronic acid (136 mg, 0.74 mmol) and 1M aqueoussolution of sodium carbonate (2 mL) at ambient temperature. Theresulting suspension was degassed with argon for 3 min andbis(triphenylphosphine)palladium(II) dichloride (47 mg, 0.07 mmol) wasadded. The mixture was heated to 80° C. and stirred for 2 hr. It wasdiluted with dichloromethane (30 mL), washed with water (30 mL) andconcentrated in vacuo. The residue was purified by flash-columnchromatography (10% methanol-dichloromethane) to1-(4-(4-(4-amino-3-(4-fluoro-3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)ethanone(188 mg, 78%). MS m/z: 482.63 (M+1).

Synthesis of Compound (10)

To a solution of tert-butyl4-(4-(4-amino-3-(4-fluoro-3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(188 mg, 0.39 mmol) in dimethylformamide (3 ml) were added phenol (56.4mg 0.60 mmol) and potassium carbonate (82.8 mg, 0.60 mmol) at ambienttemperature. The mixture was heated up to 80° C. and stirred overnight.The mixture was worked up with dichloromethane and water, concentratedin vacuo. The residue was purified by flash-column chromatography (10%methanol-dichloromethane) to1-(4-(4-(4-amino-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)ethanone(148.7 mg 68.4%). MS m/z: 557.59 (M+1).

Synthesis of Compound (11)

To a solution of tert-butyl4-(4-(4-amino-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(268 mg, 0.44 mmol) in tetrahydrofuran (5 mL) were added di-tert-butyldicarbonate (477 mg, 2.1 mmol) and 4-dimethylaminopyridine (5.3 mg, 0.04mmol) at ambient temperature. The mixture was stirred for approximately4 hours, concentrated in vacuo. The residue was purified by flash-columnchromatography (10% methanol-dichloromethane) to tert-butyl4-(4-(4-((tert-butoxycarbonyl)amino)-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(326 mg, 91%) MS m/z: 816.07 (M+1).

Synthesis of Compound (12)

To a solution of to tert-butyl4-(4-(4-((tert-butoxycarbonyl)amino)-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(50 mg, 0.06 mmol) in methanol (4 mL) was added renay nichel (100 mg)which was dispersed in methanol at ambient temperature. The round bottomflash with the mixture was degrassed with vacuum and inserted withhydrogen balloon. Repeat to degrass and supply hydrogen for 3 times. Themixture was vigorously stirred for 2 hours, and filtered with celite.Celite was washed with methanol quickly for 3 times. All elute solventwas collected and concentration in vacu. tert-butyl4-(4-(3-(3-amino-4-phenoxyphenyl)-4-((tert-butoxycarbonyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylatewas obtained. (45 mg, 95%) MS m/z: 786.28 (M+1).

Synthesis of Compound (13)

To a solution tert-butyl4-(4-(3-(3-amino-4-phenoxyphenyl)-4-((tert-butoxycarbonyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(60 mg, 0.076 mmol) in dichloromethane (0.5 mL) were added acryloylchloride (8 μL, 0.10 mmol) and 4-dimethylaminopyridine (4.0 mg, 0.033mmol) at ambient temperature. The mixture was stirred for 2 hours. Then,trifluoroacetic acid (0.5 mL) was added and stirred for another 2 hoursat ambient temperature and concentrated.N-(5-(4-amino-1-(4-(piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-phenoxyphenyl)acrylamidewas obtained (35 mg, 85%) MS m/z: 540.07 (M+1).

Synthesis of Compound (14)

To a solution of1-(4-(4-(4-amino-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)ethanone(148.7 mg, 0.267 mmol) in tetrahydrofuran (5 mL) were addeddi-tert-butyl dicarbonate (238 mg, 1.1 mmol) and 4-dimethylaminopyridine(5.3 mg, 0.04 mmol) at ambient temperature. The mixture was stirred forapproximately 4 hours, concentrated in vacuo. The residue was purifiedby flash-column chromatography (10% methanol-dichloromethane) totert-butyl(1-(4-(4-acetylpiperazin-1-yl)cyclohexyl)-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)carbamate(188 mg, 93%) MS m/z: 757.91 (M+1).

Synthesis of Compound (15)

To a solution of to tert-butyl(1-(4-(4-acetylpiperazin-1-yl)cyclohexyl)-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)carbamate(50 mg, 0.066 mmol) in methanol (4 mL) was added renay nichel (100 mg)which was dispersed in methanol at ambient temperature. The round bottomflash with the mixture was degrassed with vacuum and inserted withhydrogen balloon. Repeat to degrass and supply hydrogen for 3 times. Themixture was vigorously stirred for 2 hours, and filtered with celite.Celite was washed with methanol quickly for 3 times. All elute solventwas collected and concentration in vacu. tert-butyl(1-(4-(4-acetylpiperazin-1-yl)cyclohexyl)-3-(3-amino-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)carbamatewas obtained (48 mg, 98%) MS m/z: 728.04 (M+1).

Synthesis of Compound (16)

To a tert-butyl(1-(4-(4-acetylpiperazin-1-yl)cyclohexyl)-3-(3-amino-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)carbamate(30 mg, 0.041 mmol) in dichloromethane (0.5 mL) were added acryloylchloride (4 μL, 0.05 mmol) and 4-dimethylaminopyridine (4.0 mg, 0.033mmol) at ambient temperature. The mixture was stirred for 2 hours. Then,trifluoroacetic acid (0.5 mL) was added and stirred for another 2 hoursat ambient temperature and concentrated. The crude mixture was dilutedwith dimethyl sulfoxide DMSO (1 mL) and directly purified by preparativereverse-phase HPLC (methanol/water gradient) to provideN-(5-(4-amino-1-(4-(piperazin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-phenoxyphenyl)acrylamideas a TFA salt. (TX1-85-1) (12 mg, 50%) 1H NMR: (600 MHz, DMSO-d₆) δ(ppm): 9.94 (s, 1H); 8.38 (s, 1H); 8.32 (s, 2H); 8.23 (s, 1H); 7.37 (m,3H); 7.06 (d, J=8.4 Hz, 2H); 6.96 (d, J=8.4 Hz, 2H); 6.64 (dd, J=17.4and 10.8 Hz, 1H); 6.19 (dd, J=17.4 and 1.8 Hz, 1H); 5.69 (dd, J=10.8 and1.8 Hz, 1H); 4.91 (s, 1H); 3.42 (br m, 5H); 2.56 (br m, 4H); 2.39 (s,3H); 2.05 (m, 4H); 1.91 (br m, 4H); MS m/z: 581.43 (M+1)

Synthesis of Compound (17)

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1g, 3.83mmol) in dimethylformamide (15 ml) were added tert-butyl4-bromopiperidine-1-carboxylate (1.5 g, 5.68 mmol) and potassiumcarbonate (1g, 7.25 mmol) at ambient temperature. The mixture was heatedup to 80° C. and stirred overnight. The mixture was worked up withdichloromethane and water, concentrated in vacuo. The residue waspurified by flash-column chromatography (methanol-dichloromethane) totert-butyl4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(918.5 mg 53.8%). MS m/z: 445.76 (M+1).

Synthesis of Compound (21)

To a solution of3-(3-nitro-4-phenoxyphenyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(100 mg, 0.23 mmol) in dimethylformamide (3 mL) were added tert-butyl(2-bromoethyl)carbamate (78 mg, 0.35 mmol) and potassium carbonate (128mg, 0.93 mmol) at ambient temperature. The reaction mixture was heatedto 80° C. stirred at ambient temperature overnight. The crude was workedup with dichloromethane and water. The product was purified byflash-column chromatography (8% methanol-dichloromethane) to providetert-butyl(2-(4-(4-amino-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)ethyl)carbamate(135.2 mg, 67.2%) as a yellow solid. MS m/z: 575.62 (M+1).

Synthesis of Compounds (22) and (23)

To a solution of tert-butyl(2-(4-(4-amino-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)ethyl)carbamate(30 mg, 0.05 mmol) in dichloromethane (1.2 mL) was added trifluoroaceticacid (500 μL) at ambient temperature. The reaction mixture was stirredat ambient temperature for 2 hr and concentrated invacuo. The crudeproduct was taken up in dimethylformamide (1.0 mL), and to that solutionwere added (2R)-4-((1r,3S)-adamantan-1-yl)-2-methylbutanoic acid (10 mg,0.042 mmol), N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimidehydrochloride (30.8 mg, 0.16 mmol) and 4-(dimethylamino)pyridine (4 mg,0.03 mmol) at ambient temperature in this order. The reaction mixturewas stirred at ambient temperature for 3 hr. The residue was purified byflash-column chromatography (methanol-dichloromethane) to provide(R)-4-((3R,5R,7R)-adamantan-1-yl)-N-(2-(4-(4-amino-3-(3-nitro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)yl)ethylbutanamide(17.4 mg 50.2%). MS m/z: 693.45 (M+1).

Synthesis of Compound (26)

Following synthetic procedures described above,(R)—N-(2-(4-(3-(3-acrylamido-4-phenoxyphenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)ethyl)-4-((3R,5R,7R)-adamantan-1-yl)-2-methylbutanamide(7.3 mg) ((R)-TX2-121-1) was purified by preparative reverse-phase HPLC(methanol/water gradient). ¹H NMR: (600 MHz, DMSO-d₆) δ (ppm): 9.94 (s,1H); 9.74 (s, 1H); 8.33 (s, 1H); 8.22 (s, 1H); 7.37 (t, J=8.4 Hz, 2H);7.33 (dd, J=8.4 Hz and 1.8 Hz, 1H); 7.11 (d, J=8.4 Hz, 1H); 7.07 (d,J=8.4 Hz, 2H); 6.96 (d, J=8.4 Hz, 1H); 6.64 (dd, J=17.4 and 10.8 Hz,1H); 6.19 (dd, J=17.4 and 1.8 Hz, 1H); 5.69 (dd, J=10.8 and 1.8 Hz, 1H);4.91 (s, 1H); 3.42 (br m, 5H); 2.56 (br m, 4H); 2.39 (s, 3H); 2.05 (m,4H); 1.91 (br m, 4H); MS m/z: 717.42 (M+1).

Synthesis of Compound (36)

Following synthetic procedures described above, but using propionylchloride instead of acryloyl chloride, compound 36 ((R)-TX2-121-3) wasprepared.

Synthesis of Compound (27)

N-(5-(1-(1-(2-(2-((1s,3s)-adamantan-1-yl)acetamido)ethyl)piperidin-4-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-phenoxyphenyl)acrylamide(15.8 mg) (TX2-112-1) was purified by preparative reverse-phase HPLC(methanol/water gradient). ¹H NMR: (600 MHz, DMSO-d₆) δ (ppm): 9.95 (s,1H); 9.50 (br s, 1H); 8.37 (s, 1H); 8.29 (s, 1H); 7.37 (t, J=8.4 Hz,2H); 7.33 (dd, J=8.4 Hz and 1.8 Hz, 1H); 7.13 (d, J=8.4 Hz, 1H); 7.07(d, J=8.4 Hz, 2H); 6.76 (d, J=8.4 Hz, 1H); 6.64 (dd, J=17.4 and 10.8 Hz,1H); 6.20 (dd, J=17.4 and 1.8 Hz, 1H); 5.70 (dd, J=10.8 and 1.8 Hz, 1H);4.99 (br m, 1H); 3.66 (m, 5H); 3.38 (br m); 3.24 (br m); 2.43 (s, 3H);2.35 (m); 2.14 (br m); 1.85 (br m); MS m/z: 675.41 (M+1).

Synthesis of Compound (28)

N-(5-(1-(1-(2-(2-(2-((1s,3s)-adamantan-1-yl)acetamido)ethoxy)ethyl)piperidin-4-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-phenoxyphenyl)acrylamide(12.3 mg) (TX2-114-1) was purified by preparative reverse-phase HPLC(methanol/water gradient). 1H NMR: (600 MHz, DMSO-d₆) δ (ppm): 10.0 (s,1H); 9.66 (br s, 1H); 8.47 (s, 1H); 8.38 (s, 1H); 7.47 (t, J=8.4 Hz,2H); 7.42 (dd, J=8.4 Hz and 1.8 Hz, 1H); 7.23 (t, J=8.4 Hz, 1H); 7.16(d, J=8.4 Hz, 2H); 7.05 (d, J=8.4 Hz, 1H); 6.74 (dd, J=17.4 and 10.8 Hz,1H); 6.30 (dd, J=17.4 and 1.8 Hz, 1H); 5.79 (dd, J=10.8 and 1.8 Hz, 1H);5.10 (br m, 1H); 3.80 (m, 5H); 3.73 (br m, 4H); 3.51 (br m, 4H); 3.27(br m) 2.57 (s); 2.23 (m); 1.90 (br m); MS m/z: 719.44 (M+1).

Synthesis of Compound (29)

N-(5-(4-amino-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-phenoxyphenyl)acrylamide(5.0 mg) (TX2-120-1) was purified by preparative reverse-phase HPLC(methanol/water gradient). 1H NMR: (600 MHz, DMSO-d₆) δ (ppm): 10.0 (s,1H); 9.56 (br s, 1H); 8.42 (s, 1H); 8.30 (s, 1H); 7.473 (t, J=8.4 Hz,2H); 7.39 (dd, J=8.4 Hz and 1.8 Hz, 1H); 7.19 (t, J=8.4 Hz, 1H); 7.11(d, J=8.4 Hz, 2H); 7.03 (d, J=8.4 Hz, 1H); 6.70 (dd, J=17.4 and 10.8 Hz,1H); 6.26 (dd, J=17.4 and 1.8 Hz, 1H); 5.76 (dd, J=10.8 and 1.8 Hz, 1H);5.05 (br m, 1H); 3.80 (m); 3.70 (br m); 3.16 (br m); 2.49 (s); MS m/z:470.34 (M+1).

Synthesis of Compound (32)

To a solution of 1-methyl-1H-indole-2-carboxylic acid (75.0 mg, 0.43mmol) in dichloromethane (1.2 mL) were added oxalyl chloride (44.8 μL,0.51 mmol) and a catalytic amount of dimethylformamide at ambienttemperature. The reaction mixture was stirred at ambient temperature for2 h, and concentrated invacuo. The crude material was taken up withdichloromethane (2.0 mL), and to that solution were added4-amino-3-methoxyphenylboronic acid pinacol ester (106.6 mg, 0.43 mmol),N,N-diisopropylethylamine (111.9 μL, 0.64 mmol) and4-(dimethylamino)pyridine (5.2 mg, 0.043 mmol) sequentially. Thereaction mixture was stirred at ambient temperature for 3 hr. Themixture was diluted with dichloromethane (10 mL), washed with water andconcentrated invacuo. The residue was directly used for the next stepwithout further purification. MS m/z: 406.98 (M).

Synthesis of Compound (33)

To a solution oftert-butyl-4-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(64.0 mg, 0.12 mmol) in dioxane (1.94 mL) were addedN-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide(59.5 mg, 0.15 mmol) and 1M aqueous solution of sodium carbonate (485μL) at ambient temperature. The resulting suspension was degassed withargon for 3 min and bis(triphenylphosphine)palladium(II) dichloride (8.5mg, 0.012 mmol) was added. The mixture was heated to 80° C. and stirredfor 2 hr. It was diluted with dichloromethane (10 mL), washed with water(10 mL) and concentrated invacuo. The residue was purified byflash-column chromatography (10% methanol-dichloromethane) to providetert-butyl4-(4-(4-amino-3-(3-methoxy-4-(1-methyl-1H-indole-2-carboxamido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(55.2 mg, 66.9%) as a brown solid. MS m/z: 680.30 (M+1).

Synthesis of Compound (34)

To a solution of tert-butyl4-(4-(4-amino-3-(3-methoxy-4-(1-methyl-1H-indole-2-carboxamido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazine-1-carboxylate(33.1 mg, 0.049 mmol) in dichloromethane (1.1 mL) was addedtrifluoroacetic acid (250 μL) at ambient temperature. The reactionmixture was stirred at ambient temperature for 2 hr and concentrated.The crude product was taken up in acetonitrile (1.2 mL), and to thatsolution were added tert-Butyl N-(2-bromoethyl)carbamate (16.4 mg, 0.073mmol) and potassium carbonate (26.9 mg, 0.20 mmol) sequentially. Themixture was heated to reflux and stirred for 1 hr. The residual solidwas filtered and washed with ethyl acetate (10 mL), and the filtratedwas concentrated invacuo. This residue was purified by flash-columnchromatography (8% methanol-dichloromethane) to provide tert-butyl(2-(4-(4-(4-amino-3-(3-methoxy-4-(1-methyl-1H-indole-2-carboxamido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)ethyl)carbamate(21.6 mg, 61.6%) as a yellow solid. MS m/z: 723.33 (M+1).

Synthesis of Compound (35)

To a solution of tert-butyl(2-(4-(4-(4-amino-3-(3-methoxy-4-(1-methyl-1H-indole-2-carboxamido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)piperazin-1-yl)ethyl)carbamate(21.6 mg, 0.03 mmol) in dichloromethane (1.2 mL) was addedtrifluoroacetic acid (300 μL) at ambient temperature. The reactionmixture was stirred at ambient temperature for 2 hr and concentratedinvacuo. The crude product was taken up in dimethylformamide (1.0 mL),and to that solution were added 4-(adamantan-1-yl)-2-methylbutanoic acid(8.5 mg, 0.036 mmol), N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimidehydrochloride (17.3 mg, 0.09 mmol) and 4-(dimethylamino)pyridine (0.4mg, 0.003 mmol) at ambient temperature in this order. The reactionmixture was stirred at ambient temperature for 3 hr. The crude mixturewas diluted with water (1 mL) and directly purified by preparativereverse-phase HPLC (methanol/water gradient) to provide(R)—N-(4-(1-(4-(4-(2-(4-(adamantan-1-yl)-2-methylbutanamido)ethyl)piperazin-1-yl)cyclohexyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide(SML-11-124-1) as a mixture of cis/trans isomers (6.3 mg, 25.0%) as aTFA salt. MS m/z: 841.38 (M+1).

Biological Assays Invitrogen LanthaScreen™ Eu Kinase Binding Assay

FIG. 2 depicts binding affinity data for exemplary compounds of Formula(II). Binding affinity (IC₅₀) was measured by Invitrogen LanthaScreen™Eu kinase binding assay which is based on the binding and displacementof Alexa Fluor 647 labeled ATP-competitive kinase inhibitor scaffold(Kinase Tracer 178). Binding of the tracer to the kinase is detectedusing a europium-labeled anti-tag antibody (anti-GST). The binding ofboth the tracer and antibody to the kinase results in a high degree ofFRET (fluorescenece resonance energy transfer) from the europium donorfluorophore to the Alexa Fluor 647 acceptor fluoropore on the kinasetracer. Binding of an inhibitor to the kinase competes for binding withthe tracer, resulting in a loss of FRET. The typical experimentprocedure is shown below:

-   -   (1) Purified ErbB3(667-1053) protein was obtained from        Invitrogen at a concentration of 1.19 mg/ml. The buffer is 50 mM        Tris (pH 7.5), 150 mM NaCl, 0.5 mM EDTA, 0.02% Triton® X-100, 2        mM DTT, 50% Glycerol. Dilute to 30 nM with Kinase Buffer A (50        mM HEPES ph 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.01% Brij-35).    -   (2) 1 to 1 mix ErbB3 protein with 12 nM LanthaScreen™        Eu-anti-GST antibody solution which was also dilute in Kinase        Buffer A. Prior to use, the antibody tube should be thawed and        centrifuged at approximately 10,000g for 5 minutes, and the        solution needed for the assay should be aspirated from the top        of the solution. This centrifugation step will eliminate        spurious data points that can arise on occasion due to any        particulates in the product.    -   (3) Add 5 ul the mixture of ErbB3 protein and Eu-anti-GST to 5        ul test compound solution per well in coming 384 plates.    -   (4) Add 5 ul tracer 178 at concentration of 39 nM per well.    -   (5) Incubate for 3 hours at 4° C. and read plate with Perkin        Elmer EnVision.

CellTiter-Glo® Luminescent Assay

FIG. 3 depicts anti-proliferation data for exemplary compounds ofFormula (II). The anti-proliferation assay was carried out by using 96well white bottom plates. 2000-4000 cells were seeded per well, and themedium volume per well was about 100 ul. Incubate for 3 days afteradding and titrating indicated concentration of compounds. The cellviability was test by CellTiter-Glo® Luminescent Assay. In a typicalexperiment, add 10 ul CellTiter-Glo® reagent per well. Mix and shake theplate for 2 minutes to induce cell lysis at room temperature. Allow theplate to incubate at room temperature for approximately 10 minutes tostabilize luminescent signal. Read plate with Perkin Elmer EnVision. Thecell numbers were normalized by the DMSO control. And the EC₅₀s werecalculated by GraphPad Prism.

Electrophoretic Gel (SDS-PAGE)

FIGS. 4A and 4B depict electrophoretic gel image (SDS-PAGE) results ofcompounds TX2-112-1, TX2-113-1, TX2-114-1, TX2-120-1, and TX2-121-1(FIG. 4A) and SML-11-124-1 and TX2-126-1 (FIG. 4B) immunoblotted againstvarious antibodies; line 1: ErbB3 antibody; line 2: Phospho-Akt (Ser473)antibody; line 3: p44/42 MAPK (p-Erk1/2) antibody; line 4: T-Aktantibody; and line 5: Phospho-p44/42 MAPK (T-Erk1/2) (Thr202/Thr204)antibody. The general procedure for running this gel is provided below.

PC9 Gefitinib Resistant 4 (GR4) cells were cultured in 60 mm plate with10% fetal bovine serum (FBS), Roswell Park Memorial Institute medium(RPMI) medium. When the confluence reached 80%, cells were treated withcompounds in indicated concentration. After 4 hours, wash cells withmedium for three times. Cells were cultured for another 4 hours,followed by 3 times PBS washes. Cells were lysed with lysis buffer (25mM Tris-HCl pH 7.4, 150 mM NaCl, 1 mM EDTA, 1% NP-40, 5% glycerol, RochePhosSTOP phosphatase inhibitor cocktail tablets and Roche CompleteProtease inhibitor cocktail tablets). The cell lysate was rotatedend-to-end for approximately 30 min, centrifuged at 10,000g for 15minutes at 4° C. The supernatant was transferred to new tubes. The totalprotein concentration was measure by Pierce BCA protein assay: BCAreagent A and B were mixed with the ration of 20:1. Pipette 1 ml themixture to each disposal plastic cuvette, add 2 ul lysate. Incubate at37° C. for approximately 30 minutes. Cool all tubes to room temperature.

With the spectrophotometer set to 562 nm, zero the instrument on acuvette filled only with water. Subsequently, measure the absorbance ofall the samples with 10 minutes. Subtract the average 562 nm absorbancemeasurement of the Blank standard replicates from the 562 nm absorbancemeasurement of all other individual standard and unknown samplereplicates. Prepare a standard curve by plotting the averageBlank-corrected 562 nm measurement for each BSA standard vs. itsconcentration. Use the standard curve to determine the proteinconcentration of each unknown sample. Dilute all samples to 1.0 mg/mlwith lysis buffer. Add same volume 1:1 loading buffer to samples, heatsamples at 95° C. for 10 min. Run samples on an SDS-PAGE gel at 110V.

After transferred, the membrane was immunoblotted with antibodies: ErbB3antibody, Santa Cruz sc-285; Phospho-Akt (Ser473) antibody, CellSignaling 4058; Akt antibody, Cell Signaling 4685; Phospho-p44/42 MAPK(Erk1/2) (Thr202/Thr204), Cell Signaling 4377; p44/42 MAPK (Erk1/2),Cell Signaling 4695.

OTHER EMBODIMENTS

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is: 1-39. (canceled)
 40. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof; wherein: Ring A issubstituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; L¹ represents a linker selected from the groupconsisting of substituted and unsubstituted alkylene; substituted andunsubstituted alkenylene; substituted and unsubstituted alkynylene;substituted and unsubstituted heteroalkylene; substituted andunsubstituted heteroalkenylene; substituted and unsubstitutedheteroalkynylene; substituted and unsubstituted heterocyclylene;substituted and unsubstituted carbocyclylene; substituted andunsubstituted arylene; substituted and unsubstituted heteroarylene; andcombinations thereof; R^(H) represents a hydrophobic group selected fromthe group consisting of substituted and unsubstituted aryl, substitutedand unsubstituted heteroaryl, substituted and unsubstituted carbocyclyl,substituted and unsubstituted heterocyclyl, substituted andunsubstituted aralkyl, substituted and unsubstituted heteroarylalkyl,substituted and unsubstituted carbocycylalkyl, and substituted andunsubstituted heterocyclylalkyl L² represents a bond or a linkerselected from the group consisting of substituted and unsubstitutedalkylene; substituted and unsubstituted alkenylene; substituted andunsubstituted alkynylene; substituted and unsubstituted heteroalkylene;substituted and unsubstituted heteroalkenylene; substituted andunsubstituted heteroalkynylene; substituted and unsubstitutedheterocyclylene; substituted and unsubstituted carbocyclylene;substituted and unsubstituted arylene; substituted and unsubstitutedheteroarylene; and combinations thereof; and R^(D) is of formula:

wherein: R^(D1) is hydrogen, halogen, acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —CN, —NO₂, —OR^(D1a),—N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a), —CH₂N(R^(D1a))₂, —CH₂SR^(D1a),—C(═O)R^(D1a), —C(═O)OR^(D1a), —C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂,—C(═S)R^(D1a), —C(═S)OR^(D1a), —C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂,—C(═NR^(D1a))R^(D1a), —C(═NR^(D1a))OR^(D1a), —C(═NR^(D1a))SR^(D1a), or—C(═NR^(D1a))N(R^(D1a))₂, wherein each occurrence of R^(D1a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D1a) groups arejoined to form an substituted or unsubstituted heterocyclic ring; R^(D2)is hydrogen, halogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —CN, —NO₂, —OR^(D2a),—N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a), —CH₂N(R^(D2a))₂, —CH₂SR^(D2a),—C(═O)R^(D2a), —C(═O)OR^(D2a), —C(═O)SR^(D2a), —C(═O)N(R^(D2a))₂,—C(═S)R^(D2a), —C(═S)OR^(D2a), —C(═S)SR^(D2a), —C(═S)N(R^(D2a))₂,—C(═NR^(D2a))R^(D2a), —C(═NR^(D2a))OR^(D2a), —C(═NR^(D2a))SR^(D2a), and—C(═NR^(D2a))N(R^(D2a))₂, wherein each occurrence of R^(D2a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, or two R^(D2a) groups arejoined to form an substituted or unsubstituted heterocyclic ring; R^(D3)is hydrogen, halogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(D3a), —N(R^(D3a))₂,—SR^(D3a), —CH₂OR^(D3a), —CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a),—C(═O)OR^(D3a), —C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a),—C(═S)OR^(D3a), —C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3a),—C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), or—C(═NR^(D3a))N(R^(D3a))₂ wherein each occurrence of R^(D3a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D3a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2)are joined to form an substituted or unsubstituted carbocyclic orsubstituted or unsubstituted heterocyclic ring; R^(D4) is a leavinggroup selected from the group consisting of —Br, —Cl, —I, and—OS(═O)_(w)R^(D4a), wherein w is 1 or 2, and R^(D4a) is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; each occurrence ofR^(B) is independently hydrogen, acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, or a nitrogen protectinggroup, or two R^(B) groups are joined to form an substituted orunsubstituted heterocyclic or substituted or unsubstituted heteroarylring; each occurrence of R^(C) is independently hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(C1), —N(R^(C1))₂, —SR^(C1), —C(═O)R^(C1),—C(═O)OR^(C1), —C(═O)SR^(C1), —C(═O)N(R^(C1))₂, —NR^(C1)C(═O)R^(C1),—NR^(C1)C(═O)OR^(C1), —NR^(C1)C(═O)SR^(C1), or —NR^(C1)C(═O)N(R^(C1))₂,wherein each occurrence of R^(C1) is independently hydrogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(C1)groups are joined to form a substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring; a is 0, 1, 2, 3, or 4; andb is 0 or
 1. 41. The compound of claim 40 of Formula (II-a):

or a pharmaceutically acceptable salt thereof.
 42. The compound of claim40 of Formula (II-b):

or a pharmaceutically acceptable salt thereof.
 43. The compound of claim40, wherein Ring A is a substituted or unsubstituted phenyl.
 44. Thecompound of claim 40, wherein Ring A is a substituted or unsubstituted5- to 6-membered heteroaryl ring.
 45. The compound of claim 40, whereinRing A is a substituted or unsubstituted C₃-C₈ carbocyclyl ring.
 46. Thecompound of claim 40, wherein Ring A is a substituted or unsubstituted3- to 8-membered heterocyclyl ring.
 47. The compound of claim 40 ofFormula (II-c):

or a pharmaceutically acceptable salt thereof; wherein: each occurrenceof R^(A) is, independently, hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), or —C(═O)OR^(A1) wherein each occurrence ofR^(A1) is independently hydrogen, acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(A1) groups are joined to form an substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring; and c is 0 or
 1. 48. The compound of claim 40 of Formula (II-d):

or a pharmaceutically acceptable salt thereof; wherein: each occurrenceof R^(A) is, independently, hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), or —C(═O)OR^(A1) wherein each occurrence ofR^(A1) is independently hydrogen, acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(A1) groups are joined to form an substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring; and c is 0 or
 1. 49. The compound of claim 40 of Formula (II-e):

or a pharmaceutically acceptable salt thereof; wherein: each occurrenceof R^(A) is, independently, hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), or —C(═O)OR^(A1) wherein each occurrence ofR^(A1) is independently hydrogen, acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(A1) groups are joined to form an substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring; c is 0 or 1; and d is 0, 1, 2, 3, 4, or
 5. 50. The compound ofclaim 40 of Formula (II-f):

or a pharmaceutically acceptable salt thereof; wherein: each occurrenceof R^(A) is, independently, hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,—SR^(A1), —C(═O)R^(A1), or —C(═O)OR^(A1) wherein each occurrence ofR^(A1) is independently hydrogen, acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(A1) groups are joined to form an substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring; and c is 0 or
 1. 51. The compound of claim 40, wherein L¹represents a linker 4 to 20 consecutive covalently bonded atoms inlength, inclusive.
 52. The compound of claim 40, wherein L¹ represents alinker 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive covalentlybonded atoms in length.
 53. The compound of claim 40, wherein L¹represents a linker consisting of a combination of one or more groups ofthe formula:

wherein: each instance of n is independently an integer between 1 to 10,inclusive; each instance of m is independently 0, 1 or 2; each instanceof Q is independently —NR^(W1)—; —NR^(W1)—NR^(W1)—; —O—NR^(W1)—;—NR^(W1)—O—; —S—; or —O—; each instance of W is independently O, S, orNR^(W1); each instance of G₁ and G₂ are independently N or CH; eachinstance of R^(W1) is independently hydrogen; substituted orunsubstituted alkyl; substituted or unsubstituted alkenyl; substitutedor unsubstituted alkynyl; substituted or unsubstituted carbocyclyl;substituted or unsubstituted heterocyclyl; substituted or unsubstitutedaryl; substituted or unsubstituted heteroaryl; a nitrogen protectinggroup if attached to a nitrogen atom, or an oxygen protecting group ifattached to an oxygen atom; each instance of R^(W2) is independentlyhydrogen; substituted or unsubstituted alkyl; substituted orunsubstituted alkenyl; substituted or unsubstituted alkynyl; substitutedor unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; substituted or unsubstitutedheteroaryl; or two R^(W2) groups are joined to form a 5-6 membered ring;and each instance of R^(W3) is independently hydrogen; halogen;substituted or unsubstituted alkyl; substituted or unsubstitutedalkenyl; substituted or unsubstituted alkynyl; substituted orunsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl;substituted or unsubstituted aryl; or substituted or unsubstitutedheteroaryl, or two R^(W3) groups are joined to form a 3-6 membered ring;or R^(W1) and R^(W3) are joined to form a 5-6 membered heterocyclicring.
 54. The compound of claim 40, wherein R^(H) is a group of formula:

wherein each occurrence of R^(H1), R^(H2), and R^(H3) is independentlyhalogen, alkyl, haloalkyl, alkoxy, or dialkylamino; and p and q areindependently 0, 1, 2, or
 3. 55. The compound of claim 40, wherein R^(H)is a group of formula:

wherein each occurrence of R^(H1) and R^(H2) is independently halogen,alkyl, haloalkyl, alkoxy, or dialkylamino; and p and q are independently0, 1, 2, or
 3. 56. The compound of claim 52, wherein -L¹-R^(H)represents a group of the formula:

wherein each instance of G₁ and G₂ are independently N or CH.
 57. Thecompound of claim 52, wherein -L¹-R^(H) represents a group of theformula:

wherein each instance of G₁ and G₂ are independently N or CH.
 58. Apharmaceutical composition comprising a compound of claim 40, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 59. A method of treating a cancer associated withaberrant activity of a Her3 protein kinase, the method comprisingadministering a compound of claim 40 or pharmaceutical compositionthereof to a subject in need thereof in an amount sufficient to reduceHer3 protein kinase activity.